MXPA98010888A - Artificial structures of nucleic acids for gene therapy, whose activity is influenced by cicli dependent kinase inhibitors - Google Patents

Abstract

Artificial structures of nucleic acids are disclosed for the gene therapy of diseases, which contain nucleic acids encoding a protein, which inhibits the p27 cellular protein and thereby suppresses the inhibition of the proliferation of the cell that is produced by p27, a mutant thereof. dominant interfering character and the use of these nucleic acids for the prophylaxis and therapy of disease

Description

Artificial structures of nucleic acids for gene therapy, whose activity is influenced by inhibitors of cyclin-dependent kinases The present application relates to a protein, which inhibits the p27 cellular protein and thereby suppresses the inhibition of the proliferation of the cells, which is produced by p27, to mutants of it with a dominant interferential character, to the corresponding ones nucleic acids that encode it, and the use of protein and nucleic acids for prophylaxis and disease therapy. In addition, artificial nucleic acid structures are disclosed for gene therapy of diseases, which contain the aforementioned nucleic acids.

A) Introduction The cell cycle of eukaryotic cells is controlled by cyclin-dependent kinases ("cyclin-dependent kinases" = cdk's); These are "guinases" that require a regulatory subunit ("cyclin") for their activity. Different processes in the cell cycle (such as, for example, replication, entry into mitosis) are controlled by different cdk's (Morgan, Nature 374, 131 (1995)) This regulates the activity of cyclin-dependent kinases at a high level, in this context there are internal control mechanisms, which prevent, for example, entry into mitosis, as long as the DNA has not been Completely replicated Control by external factors, such as for example growth factors, takes place exclusively before the start of DNA replication, replication that is initiated by active complexes of cyclin E and cdk2, together with the amount of cyclin existing in the kinase subunit, the activity of cyclin-dependent kinases is regulated by small inhibitory proteins (Sherr and Roberts, Gene Dev. 9, 1, 149 (1995)). Two inhibitory agents are decisive for the cyclin E and cdk2 complex, which according to their size are designated p21 and p27. In cells, which express large amounts of p27, the cyclin kinase E / cdk2 is normally inactive and entry into DNA replication is blocked. In many human tumors, positive regulators of the cell cycle are overexpressed or at least constitutively expressed (Sherr, Science 274, 1, 672 (1996)) but negative regulators are frequently mutated or weakly expressed (Fero et al., Cell 85., 733 (1996)).

There are specific correlations: for example, overexpression of the cyclin DI gene is found in many cervical tumors. Therefore, there is hope that the cyclin-dependent kinases and their function could be target structures in the search for new substances that are selectively active and act antiproliferative. The gene for the p27 protein has been known for some years (K. Polyak et al., Cell 78_, 59-66 (1994)) and is accessible in the gene bank [murine p27; accession number K 09968; human p27: accession number K 10906]. In spite of the intense search, mutations in the p27 gene in human tumors have not been found until now. This is all the more surprising in that mice, in which the p27 gene has been deactivated, have a phenotype with multiple dysplasias and increased incidence of tumors (Fero et al., Cell 8J5, 733 (1996), Kiyokawa and collaborated). Res, Cell 8J, 721 (1996)). Instead, the function of p27 is manifestly regulated essentially after transcription. Thus, p27 is decomposed by proteolysis; this also happens at the beginning of DNA replication of normal cells. The ability to decompose proteolytically at p27 is clearly increased in many tumors compared to normal tissue and this seems to be directly correlated with an unfavorable prognosis (Loda et al., Na ture Med. 3, 231 (1997)). However, there must still be other mechanisms that can lead to the deactivation of p27. For example, after transformation of cells by the Myc oncogene, p27 is first functionally deactivated (ie, it no longer binds to cyclin and cdk complexes), but is decomposed only much later. Until now, it is inexplicable why in a series of tumors, for example those of the breast, high amounts of p27 proteins are expressed, and these tumors, nevertheless, grow very rapidly. The mechanisms, which deactivate the p27 in these tumors, are unknown until now (Fredersdorf et al., Proc. Nati, Acad. Sci. USA 94, 6. 380 (1997)). There is therefore a great interest of the scientific world in discovering mechanisms or substances that are responsible for the deactivation of p27 in tumors. With the present invention this problem was solved. Pl63 protein, described in the application, can bind to p27, inhibit the function of this p27, and drive p27 to proteolysis in the cytoplasm.

B) General description of the invention 1) Pl63 protein and its nucleic acid sequence The object of the invention is a new protein, called pl63, which binds to p27, thereby inhibiting its function and leading to proteolysis in the cytoplasm. The amino acid sequence of this protein was determined. Pl63 protein binds specifically to p27 and not to other proteins such as Myc, Max, Bcl-6 or protymosin-a.

The object of the invention is also a nucleotide sequence encoding the pl63 protein. This nucleotide sequence was determined for the mouse pl63 protein and, by comparison between sequences, also for the human l63 protein. 2) Dominant Negative Pl63-like Compounds The object of this invention is furthermore nucleotide sequences, which encode partial p63 peptides and / or p63-like proteins which act in a dominant negative manner, that is to say they inhibit the binding of the natural protein p63 to the p27 protein, without essentially impairing the binding of the p27 protein with the fusion of cyclin C and cdk2 nor to the inhibition of this fusion of cyclin C and cdk2 conditioned by it. - The object of the invention is furthermore the use of nucleic acid sequences, which encode dominant negative mutants of the pl63 protein or partial sequences thereof, this use involving the introduction of these nucleic acid sequences into a target cell and the inhibition of the binding between the p163 protein of this target cell and the p27 protein of this target cell, so that the proliferation of the target cell is inhibited by the p27 protein of this target cell, which is released. 3) Peptides, which inhibit the pl63 The object of this invention, however, is also nucleotide sequences, which encode proteins or peptides, which inhibit the function of the p63. These include proteins or peptides, which bind to the binding site of the p63 protein for the p27 protein or to the binding site of the p63 protein for the Ran protein (Loeb et al Mol. Biol. 4, 209-222 (1993 )) and thereby inhibit the internal protein p63 in the cell. These proteins belong to the peptides, which correspond to the binding site of the p27 protein or the Ran protein for the p63 protein. To these proteins also belong antibodies or dissociation products of antibodies, such as F (ab) 2 / Fab, Fv and scFv with specificity against the p66 protein, especially against the binding site of etane for the p27 protein. The object of the invention is furthermore the use of nucleic acid sequences that encode such inhibitory proteins or peptides, this use involving the introduction of these nucleic acid sequences in a target cell and the inhibition of the binding between the own protein pl63 of this target cell and the p27 protein of this target cell or the Ran protein of this target cell, in such a way that the proliferation of the target cell c: r is inhibited by the p27 protein of this target cell, which is released . 4) Use of pl63 for the stimulation of cell division The object of this invention is also the use of the nucleotide sequence that encodes the p63 protein, or that of the p133 protein itself, for the inhibition of the internal p27 protein in the cell and therefore for the stimulation of the cell division of a target cell.

) Inhibition of transcription and translation of pl63 They are objete; ? the _r.v-. However, also nucleic acid sequences, which inhibit the transcription and / or translation of the nucleic acid sequence, specific to the target cell, which encode the pl63 protein, and thereby lead to a release of the p27 protein and consequently to an inhibition of the proliferation of the target cell. Such nucleic acid sequences according to the invention can for example be an antisense (triplex) DNA, an antisense RNA and / or ribozymes. 6) Test systems for the discovery of p63 inhibiting agents The object of the invention is furthermore the use of the nucleic acid sequence encoding the p63 protein, or that of this protein, itself or of partial sequences thereof, for assay systems, in which inhibitors of the binding between the pl63 protein and the p27 protein or the Ran protein are sought, and the use of the inhibitors of the p63 protein, found in these test systems, for the inhibition of the proliferation of a target cell. 7) Detection of the pl63 for the diagnosis of a disease The invention also relates to the use of artificial nucleic acid structures encoding the p63 protein or partial sequences of the pl63 protein, or nucleic acid sequences or protein sequences that are join these nucleic acid sequences for the pl63 protein, or proteins that bind to the pl63 protein for the detection of nucleic acids encoding the pl63 or for the detection of the pl63 protein in a cell or in a tissue or in a body fluid, in order to determine the state of proliferation of a cell or a tissue or to make the diagnosis of a morbid state (of illness). 8) Expression systems containing binding sequences for p27 or for complexes of proteins p63 and p27 It is furthermore an object of the invention to provide an expression system which contains a nucleic acid sequence whose expression is controlled by the p27 protein and which The simplest case contains the following components: Component a) at least one activation sequence (promoter n ° 1) Component b) - at least one gene for a transcription factor consisting of a fusion protein containing component b-) at least one activation domain of a transcription factor component b2) 1) at least one sequence or at least a partial sequence of the p63 protein, to which the p27 protein binds, or ) at least one antibody or at least one antibody fragment such as Fab, Fv or scFv, which binds to the binding site of the p27 protein for the p63 protein, or 3) at least one antibody or at least one fragment of antibody such as Fab, Fv or scFv, which binds to the binding site of the p63 protein for p27 protein, or 4) at least one antibody or at least one antibody fragment such as Fab, Fv or scFv, which binds to the complex of pl63 and p27. Component b3) at least one DNA binding domain of a transcription factor Component c) - - at least one activation sequence (promoter No. II), which is activated by binding of the transcription factor, encoded by component b) Component d) - at least one effector gene.

The arrangement of the individual components is reproduced by way of example in FIG. 1. It is a premise for the functional capacity of the expression system according to the invention, that the component b2l), b22) or b23) to be brought together, between or to the components b -j_) and bj), in such a way that the binding of the p27 protein or the p63 protein to the expression product of component b2) inhibits the functional capacity of the activation domain [component b ^)] and / or the domain of DNA binding [component 3)]. This inhibition leads to an inhibition of the expression of the effector gene in cells, in which free p27 or free p63 is present. In cells, in which the p27 protein and / or the pl63 protein have been converted into complexes (complex ado), so that they can no longer interact with the component b2), or yet no longer are present (or are present only), this inhibition is lacking, in such a way that the transcription factor [component b)] can activate without obstacles the activation sequence [component c)] and with this I can start the transcription of the effector gene. A special feature is component b24). By joining fusions of pl63 and p27 with component b24; in cells that are dividing the transcription factor is inhibited ~ [component b)], and conversely in cells that are at rest (ie in the case of free p27) the transcription factor is free [component b) ] and is fully capable of functioning. The transcription of the effector gene is initiated by activation of the activation sequence [component a)], which results in an expression of the gene for the transcription factor [component b)]. The transcription factor [component b)], in turn, binds to the activation sequence [component c)], which induces an expression of the effector gene [component d)]. In a special embodiment of this invention, component a) is equal to component c). In this special embodiment, a small activation of the activation sequence [promoter I, component a)] leads to an expression of the transcription factor [component b)], which activates both the activation sequence [promoter I, component a)] as well as the activation sequence [promoter II, component c)] and thereby both induce the expression of jen for the effector gene [component d)] and also reinforce the expression of the transcription factor [component b] ? ], which in turn reinforces the expression of the effector gene [component d)]. This expression system can be extended by the juxtaposition of several identical or different sequences for effector genes [components d), d '), d ", which are linked in each case by the same or different IRES sequences or by sequences of activation [components c ') and c ")], - by the juxtaposition of several identical or different genes for transcription factors [component b)], which in each case are linked to each other by IRES sequences or activation sequences [component a ) or component c)], same or different. In the case of a juxtaposition of genes for different transcription factors, the activation sequences must be chosen in such a way that they contain nucleotide sequences, to which the transcription factor can be linked [component b)]. By means of the artificial nucleic acid structures according to the invention, an effector gene [component d)] can be expressed depending on the choice of the activation sequence [components a) or c)] in a nonspecific manner, specific for cells or specific for viruses, or in certain metabolic conditions or also specifically for a cell cycle. In the case of the effector gene, it is a gene, which in turn encodes a substance with pharmacological activity or yet encodes an enzyme, which unfolds an inactive compound precursor of a drug to give an active drug. For example, the effector gene can be selected such that this active substance or this enzyme is expressed as a fusion protein with a ligand, and a this ligand with the surface of cells, for example endothelial or tumor cells, or leukocytes . The artificial structures of nucleic acids according to the invention, which have been described, preferably consist of DNA. The term "artificial nucleic acid structures" refers to artificial structures based on nucleic acids, which can be transcribed in the target cells. These are preferably introduced into a vector, with plasmid vectors or viral vectors being especially preferred. The artificial nucleic acid structure, optionally introduced into a vector, is administered to a patient for the prophylaxis or therapy of a disease. The administration can be carried out orally, locally or by injection or infusion. The subject of the present invention are also mammalian cells, which contain an artificial nucleic acid structure according to the invention. In a particularly preferred embodiment, artificial nucleic acid structures are introduced into cell lines, which after transfection can be used as supports for the expression system according to the invention for the expression of the effector gene. Such cells can be used to make a medicine available to patients. Alternatively, the cells or cell lines, such as p. ex. Tumor, immunological or endothelial cells, in which the artificial structures of nucleic acids according to the invention have been incorporated, can be administered locally or can be injected parenterally, for example intravenously, intraarterially in a body cavity, in an organ, or can be injected subcutaneously, to patients.

A preferred use of the artificial nucleic acid structure according to the invention therefore consists in the prophylaxis or treatment of a disease, the invention comprising the introduction in vi tro of an artificial nucleic acid structure in a target cell, the mespecific expression, specific for viruses or target cells, metabolically specific and / or specific for cell cycles, of the drug in the target cell, and local or parenteral administration of the target cell to patients, or local or parenteral administration of the artificial nucleic acid structure to the patients, for the in vivo introduction of an artificial nucleic acid structure in the target cell. The artificial structures of nucleic acids according to the invention do not occur in nature in this form, ie the effector gene for the active substance, either for an enzyme or for a fusion protein of a ligand and an active substance or a ligand and an enzyme are not combined in a natural way with nucleic acid sequences, such as those contained in the artificial nucleic acid structure according to the invention. Preferred effector genes [component d)], which are incorporated in an expression system according to the invention, encode a substance with pharmacological activity. These are proteins and glycoproteins, selected from the group that contains cytokines, growth factors, receptors for cytokines or growth factors, antibodies or fragments of antibodies, proteins that act antiproliferately or cytostatically, proteins that act apoptotically or antiapoptically, tumor antigens, angiogenesis-inhibiting agents, thrombosis-inducing proteins, coagulation-inhibiting agents, proteins with fibrinolytic activity, blood plasma proteins, complement-activating proteins, envelopes-of viruses and bacteria, hormones, peptides active on circulation, neuropeptides, enzymes, mediators, regulatory proteins and unmodified ribozymes, which occur in nature, or nucleotide (antisense) sequences that act by inhibiting the expression of genes. Preferably, in the case of ranssén, it is an effector gene that encodes a ribozyme, which inactivates the mRNA (messenger ribonucleic acid), which encodes a protein selected from the group that contains proteins that control the cell cycle, especially cyclin A, cyclin B, cyclin DI, cyclin E, E2F1-5, cdc2, cdc25C, pl63 or DPI, or virus proteins or cytokines, or growth factors or their receptors. In another embodiment, the effector gene can encode a fusion protein of a ligand and an active substance, the ligand being able to be an antibody, an antibody fragment, a cytokine, a growth factor, an adhesion molecule or a peptide hormone, and the active substance being able to be a substance with pharmacological activity, as described above, or an enzyme. For example, the effector gene can encode a fusion protein of a ligand and an enzyme, by unfolding the enzyme to a precursor compound of a drug to form the drug and binding the ligand to a cell surface, preferably to that of endothelial cells or tumor cells.

C) More detailed description of the invention 1) Characterization of the pl63 protein and the nucleic acid sequence encoding the pl63 protein With the help of "two-hybrid technology" [= two-hybrid-Technologie] (Fields and Song, Nature 340, 245 (1989)) Pl63 protein was revealed as a new p27 participant protein. For this, the whole coding sequence of the murine p27 protein was cloned with the help of a PCR (polymerase chain reaction) in the yeast vector pGBTIO (Clontech) within the frame with the DNA binding domain of the transcription factor. GAL4. The yeast strain Hf7c (entity Clontech Heidelberg, Matchmaker two Hybrid, K 1605-1) was transformed with this vector, auxotrophic colonies for tryptophan were isolated, and the expression of the correct fusion proteins was detected in the Western blot with the help of specific antibodies against GAL4 and p27. This strain was transformed, in a second transformation, with a cDNA library labeled with VP16, derived from mouse embryos (Voj tek et al., Cell 7_4, 205 (1993)). We further analyzed 400 colonies, which were auxotrophic for histidine, in the presence of 15 nM aminotriazole. Seventy of these clones were sequenced; they all encoded different type D cyclins; these are known participants in p27 interactions. With the aid of Southern blots it was revealed that 390 of the 400 resistant clones encoded cyclin D. Two of the remaining clones ("number 163") encoded the same protein; these were completely sequenced. From a ΔZAP cDNA library, produced from Balb / c-3T3 cells, several clones were identified, which were homologs with pl63. The analysis of the sequences shows an open reading frame; it is also used in the chimera with VP16 from the cDNA library. Both original clones encode amino acids 121 to 252 of this reading frame. Pl63 clones were characterized in greater detail with ß-galactosidase as a reporter gene in yeast. As depicted in Table 1, the encoded protein interacts in yeast specifically with p27, but not with other proteins, such as Myc, Max, Bel-6 or protymosin. Table 1 also shows a first delimitation of the domains of p27, in which the interaction with pl63 takes place. These data point to the fact that pl63 binds to the same domains of p27 as cyclin-dependent kinases (Russo et al., 382, 325 (1996)). This is an indication that p63 and cyclin-dependent kinases compete for their binding to -p27. On the other hand, the domain of pl63, which interacts with p27, could be delimited to amino acids 121 to 252.

For confirmation of these results from this yeast assay system, a recombinantly expressed p163 [expressed as glutathione transferase fusion protein (GST)] was fixed to a column and then purified by affinity chromatography in this column. column to the p27 protein labeled with 35S. By using the pl63 fusion protein with a glutathione transferase (GST) it was possible to use a uniform matrix for these experiments (so-called "GST-pulldowns", Hateboer et al., Proc. Nati Acad. Sci. US 90, 8. 489 (1993)). For these investigations, the reading frame was transferred from the clone in yeast to a pGEX vector (Pharmacia, Freiburg pGEX-2T, order no 27-4801-01), which encodes a chimeric glutathione protein in E. coli S-transferase (GST) under the control of the TAC promoter inducible by IPTG (Smi th and Johnson, Gene 67: 31, 1988). The chimeric proteins were purified from cultures in induced E. coli, by affinity chromatography on glutathione-agarose (Smi th and Johnson, 1988) and then dialysed against 100 mM Tris-HCl, pH 7.5, KCl 100 mM, 20 mM EDTA, 10% glycerol and 0.1 mM PMSF. As a control, glutathione S-transferase was purified and dialyzed according to the same protocol; the purified proteins were stored at -80 ° C. In each case 10 μg of both proteins were then incubated for two hours at 4 ° C with 10 μg of BSA [= bovine serum albumin] and 20 mg of swollen GST-agarose; after that the agarose was separated by centrifugation and washed twice with a dialysis buffer. As a control for the binding of the proteins, an aliquot of the agarose was boiled directly in a sample buffer and the bound proteins were detected according to an SDS-gel electrophoresis. A p27 labeled with 35S-methionine was prepared by in vitro translation (according to the manufacturer's data: Promega, Mannheim, TNT coupled rete.lysystems: L 4610) and incubated with charged agarose for two hours in one volume total of 200 1 in a dialysis buffer with 0.1% NP40 at 4 ° C. The agarose was washed four times with a mixture of a dialysis buffer and 0.1% NP-40 and then boiled in SDS-sample buffer. The bound proteins were detected by SDS-gel electrophoresis and fluorography. The results of these experiments are shown in Table 2. These show that a recombinant p27, marked with S, synthesized in vi tro, is selectively fixed to a column, which is loaded with a chimeric fusion of GST and pl63, but not to a column that is loaded with the same amount of GST. Table 2 also demonstrates that a p27 from a cell extract binds inefficiently to a fusion of GST and p63; in this extract, p27 is linked to cyclin-dependent kinase complexes. A short heat treatment releases the p27 from these complexes and then allows the union to the pl63. This shows that p63 and cyclin-dependent kinases compete for binding to p27. The nucleotide sequence according to the invention, which encodes the murine pl63 protein, is represented in Table 3. This sequence has a homologue in the data bank; it is the nucleoprotein gene (Nup) 2 of the yeast. Nup2 is a protein of the core membrane, which participates in the formation of the core protein and in the transport of proteins in and out of the nucleus. Nup2 participates well in yeast, especially in export. Several functional domains are conserved, even though, overall, the homology is not high (Table 4). Thus, the binding site for a regulatory protein (Ran, which is a protein that binds to GTP), which regulates transport in the nucleus, is conserved between the Ran binding protein (RBP-1) [Ran binding protein ], Xup2 and pl63 (Table 5), as well as short sequences of pentapeptides, to which a structural function is attributed (Table 6). ZZ T. In order to verify and demonstrate that the pl63 consists without a doubt in a nucleoporin, a poly- antial antiserum was generated against the protein [histidine-pl63 (aa [= amino acids] 121-252)] and was purified by affinity; this antiserum undoubtedly recognizes a nucleoporin, which is recognizable- in the immunofluorescence by the typical coloration of the pores in the nucleus (there are "specks" on the surface, and the periphery of the nucleus is colored). To verify an intracellular association between il 2 D Nup2 and p27, both proteins were expressed transiently in HeLa cells with CMV expression vectors, 48 hours later the cells were lysed and investigated for a possible interaction of both proteins by immunoprecipitation and / or Western blots (Peukert et al., EMBO, J, 1, 5. 672 (1997)). The association between p27 and Nup2 was checked with both polyclonal antibodies against Nup2 and against murine p27. The p27 protein was well precipitated only in the case in which p63 was expressed (see Table 7). This is a proof that Nup2 and p27 can be associated with each other within HeLa cells. By comparing sequences and searching for data with human ESTs, the nucleic acid sequence for the human pl63 protein was identified. For the domain binding to Ran, it is in the sequence AA161285 at positions 173 = 575, for the binding domain to p27 in the sequence R62312 at positions 318 ¿486, and for the other partial segments of p63 in the sequence THC199124 at positions 348 > 489. In order to define more precisely which amino acids of p27 the interaction between Nu 2 and pl63 takes place, mutants that no longer interact with p63 were searched for in yeasts. For this, the cDNA, which encoded p27, was subjected to a defect-inducing PCR reaction (PCR conditions according to "PCR-technology, Principies and Applications for DNA amplification ", RA, Eriich, Stockton press, NY, 1989) and the resulting clones, which contain random defects, were tested for an interaction with Nup2 and, as a control, with cyclin DI. PCR (deviating from the standard) were: 40 cycles in the presence of 1 U of GIBCO Taq polymerase and 0.1 mM MnCl2 The obtained cDNA fragment was transformed together into the yeast strain HF7c-pl63 / Nup2 with a pGBTIO vector, which had been linearized with BamHl and EcoRI and purified.The transformed colonies were selected by selection from a missing medium -Leu-Trp .960 individual clones were isolated and plated on medium Selective (-Leu-His-Trp) With the clones, which did not grow on this selective medium, was carried out -an assay with β-galactosidase as the second interaction assay.The negative clones were identified and from them was isolated the plasmid pGBT10-p27. The plasmids obtained were first transformed with an expression plasmid in yeast, which expresses the fusion of pl63 and Nup2 as a chimera with a transactivating domain, and secondly as a control with a plasmid expressing cyclin DI as a chimera with a transactivator domain. Three clones were obtained, which no longer interact selectively with Nup ~ 2, but with cyclin DI. These plasmids were sequenced together with some controls. A selection of the phenotype obtained is compiled in Table 13. In these experiments an interaction is revealed as growth in the absence of histidine (-Trp-Leu-His, "selective"), while the control (-Trp-Leu, - "non-selective") shows that both proteins had been expressed in yeast. Out of 1,000 clones, 3 were found, which no longer interact specifically with the fusion of p63 and Nup2 but perfectly with cyclin DI. The sequences are shown in Table 14. The three clones, but not a series of control clones, carry the same mutation in the amino acid arginine 90 (rautadc to glycine). The sequences also show that the hundreds have been formed independently, since they are carriers of other diverse mutations. Accordingly, arginine 90 is unequivocally defined as a central amino acid in the interaction of p27 with Nup2. The mutants are available for a validation of the biological relevance of this interaction. 2) Nucleotide sequences for compounds analogous to the p63 protein that act in a dominant negative manner. By means of the functional analyzes described above, two domains of the p63 protein have been known, which are decisive for their function. On the one hand, it is the domain (amino acids 121-252) for binding to p27. On the other hand, it is the domain (amino acids 307-467) for binding to Ran, which is a protein that binds to GTP, which regulates transport functions. Therefore, nucleic acid sequences for the pl63 protein or for parts of this protein are subject of the invention, these nucleic acid sequences having mutations in the p27 binding domain and / or in the Ran binding domain, therefore, the binding of the expressed mutated protein to either p27 or Ran is drastically decreased. Introduced into a cell, such p663-like compounds inhibit the cell's own p63, capable of functioning. With this, free p27 is formed, which leads to the inhibition of cell division. Examples of such dominant p63-negative mutants are shown in Tables 8 and 9. Table 8 shows p63 with a deletion of the p27 binding domain and Table 9 shows pl63 without the poma binding domain. It is therefore the object of the invention to introduce artificial nucleic acid structures encoding dominant p63-negative analogs in a cell, with the goal of inhibiting the proliferation of this cell. This introduction into the cell can be carried out in vi tro but also in vivo. For the best possible and / or controlled expression of the artificial nucleic acid structure according to the invention, this is preferably linked to an activation sequence. Examples of such activation sequences are discussed in paragraph 8.3. For localization in the nucleus, a nuclear localization signal (NLS = Nukleáres LokalisationSignal) must be attached to the nucleic acid sequence, which codes for the pl63. Such NLS are known to one skilled in the art. The artificial nucleic acid structure is incorporated into the cell as "naked" DNA either with the aid of a non-viral vector, or with the help of and introduced into a viral vector, according to procedures known to a person skilled in the art. . 3) Nucleotide sequences for proteins or peptides, which bind to the binding domain of the p63 With the above-mentioned investigations, the p27-binding domain domain of the p63 protein could be established and fixed at amino acids 307-467 amino acids 121-252 and the domain binding to the Ran. Therefore, artificial nucleic acid structures encoding peptides, which either bind to the binding domain of pl63 for p27, and thus inhibit the binding of pl63 to p27, or bind to the p27, are therefore subject of the invention. union domain of the pl63 to the Ran and thereby inhibit the union of the pl63 to the Ran. By means of this inhibition, free p27 is formed, which inhibits cell proliferation by binding, for example, to the fusion of cyclin E and cdk2. An example of a peptide that inhibits it in such a way is constituted by amino acid sequences, which correspond to the p63 binding domain of the p27 protein (amino acids 69-178) or of the Ran. Another example is antibodies or fragments of human antibodies, such as F (ab) 2, Fab, Fv or scFv, which bind to p63, in particular to the p27 binding domain or to the binding site to the Ran of ia. pl63 Such antibodies can be obtained, for example, by immunization of animals with p63, or with the domain of an α to p27 or with the domain binding to Ran, of p63. These domains are represented in Table 5 (Ran domain) or in Table 10 (domain binding to 2 ~. Therefore, the introduction of artificial nucleic acid structures encoding proteins that bind to the p63, within a cell, with the goal of inhibiting the proliferation of this cell.This introduction into the cell can be carried out in vi tro but also in vi. For the best possible expression and / or of the artificial nucleic acid structure according to the invention, this is preferably linked to an activation sequence Examples of such activation sequences are set forth in paragraph 8.3 For location in the nucleus, it is to be attached to the sequence of nucleic acid, which encodes the artificial nucleic acid structure according to the invention, a nuclear localization signal (NLS) Such NLS are known to a person skilled in the art. The nucleic acid is introduced into the cell as "naked" DNA, or with the help of a non-viral vector, or with the aid of, and introduced into, a viral vector, according to methods known to a person skilled in the art. 4) Nucleotide sequences for pl63 in order to stimulate cell division - The introduction into a cell of the nucleotide sequence for pl63 or the pl63 protein leads to the inhibition of intracellular p27. This releases cyclin E and cdk2 complexes (which are inhibited by p27), which initiate cell division. The object of the invention is therefore the introduction of artificial structures of nucleic acids encoding pl63 in a cell, with the goal of promoting the proliferation of this cell. This introduction into the cell can be carried out in vi tro but also in vivo. For the best possible and / or controlled expression of the artificial nucleic acid structure according to the invention, it is preferably linked to an activation sequence. Examples of such activation sequences are indicated in paragraph 8.3. For localization in the nucleus, a nuclear localization signal (NLS) must be attached to the nucleic acid sequence encoding the pl63. Such NLS are known to one skilled in the art. The artificial nucleic acid structure is incorporated into the cell as "naked" DNA either with the aid of a non-viral vector, or with the help of and introduced into a viral vector according to methods known to a person skilled in the art. . By introduction of an artificial nucleic acid structure encoding the pl63, proliferation may be incited for example cells in the cell culture or cells in vivo, e.g. ex. in the case of defective cell proliferation.

) Nucleotide sequences for the inhibition of transcription and / or translation of the pl63 protein Knowledge of the nucleic acid sequence of the p63 protein offers the possibility of producing oligonucleotides with the help of which transcription or translation can be specifically inhibited from pl63. To these antisense nucleic acids belong oligonucleotides, DNA (triplex) antisense, ribozymes or antisense RNA. The method for the preparation of triplex DNA oligonucleotides has been described in detail by Frank-Kamenetskii and Mirkin, in Ann. Rev. Biochem. 64, 65 (1995) and the method of the preparation of anti-sense RNA molecules has been described by Neckers et al., In Critic Rev. Oncogen, 3, 175 (1992), Cárter and Lemoine, In br. ". Cancer 67, 869 (1993), Mukhdopadhyay and Roth, Crit. Rev. Oncogen. 7, 151 (1996) and Mercóla y Cohén, Cancer Gene Ther. 2, 47 (1995). Preferably, triplex DNA or antisense RNA oligonucleotides, which hybridize with pl63 nucleotide sequences, which encode partial areas of the binding domain (total zone, amino acids 121-252; p27 protein or partial areas of the binding domain (total area amino acids 307-467) for the Ran protein.To the nucleotide sequences that inhibit the transcription and / or translation of pl63, ribozymes also belong specifically to regions of the sequence of nucleotides of the p63 protein The method for the preparation of ribozymes was described in detail by Burke, in Nucí Acids, Biol. 105 (1994), Christoffersen and Marr, in J. Med. Chem. , 38, 2. 023 (1995) and Scott et al., In Science 274, 2. 065 (nineteen ninety six) . Preferred in the sense of the invention are ribozymes, "which hybridize with pl63 nucleotide sequences, which are located in the region of the nucleotide sequence for the binding domain (amino acids 121-252) for the p27 protein, or for the binding domain (amino acids 307-467) for the Ran protein Examples of nucleotide sequences of the pl63 protein, cleavable by ribozymes, are set forth in Table 11.

The triplex DNAs, antisense RNAs or ribozymes, such as oligonucleotides [prepared and protected against degradation by DNases or RNases according to methods known to a person skilled in the art (see above-mentioned biDiography)] or are added in vi tro to the cells target or - are administered in vivo by injection or local application. The object of the invention is, however, also the introduction of artificial structures of nucleic acids into a cell, with the goal that antisense RNA or ribozymes corresponding to the oligonucleotides according to the invention are formed in the cell by transcription, in order to inhibit the proliferation of this cell. The introduction into the cell can be carried out in vi tro but also in vivo. For the best possible and / or controlled expression of the artificial nucleic acid structure according to the invention, it is preferably linked to an activation sequence. Examples of such activation sequences are set forth: paragraph 8.3. The artificial nucleic acid structure is incorporated into the cell as "naked" DNA or with the aid of a non-viral vector, or with the help of, and introduced into, a vector in this vector, according to the known methods of the invention. an expert in the field. 6) Test systems for the discovery of inhibitors of the function of pl63 The discovery of the pl63 protein and its interaction with the protein p27 makes it possible to search for inhibitors of this interaction. , in which the binding between protein 27 and protein pl63 is inhibited and this inhibition is indicated by an indicator Many methods are known An example of one of these methods is the "two-hybrid screening assay" [= " Two Hybrid Screen A'ssay "] (see paragraph Cl and Table 1 for this)., however, an affinity system can also be used for the screening, in which the pl63 [preferably the p27 binding domain (amino acids (121-252)] is bound to a solid phase, is incubated with The substance under test is determined, and the binding of the substance under test is determined by inhibiting the binding of a labeled partner at the junction to the p27 protein domain that binds to p27. be the p27 or an antibody that binds specifically to the domain of the pl63 protein that binds to p27.Also that for the inhibitors of the junction between the pl63 and the p27 can also be constituted test systems for inhibitory agents of the link between p63 and Ran, and can be used for counting.It is the object of the invention therefore the use of nucleic acid sequences, which encode pl63 or partial p63 proteins, or the use of prot eine pl63 or partial proteins of this one, for the search as for inhibitors of p63. 7) Use of the nucleic acid sequence for pl63, or of the pl63 protein sequence, to diagnose the stage of proliferation of a cell or a morbid state As depicted in the introduction, paragraph A), a Tumor series are distinguished by an intracellular concentration, increased by p27. Because of the fact that these tumors proliferate, it is to be assumed that the function of this increased p27 is inhibited. Correspondingly to this invention, pl63 is the p27 specific inhibitory agent. The detection of this inhibitory agent in a cell makes it possible to make a statement about the state of proliferation of the cell. This statement can be very important p. ex. for the evaluation of the malignancy of a tumor cell or a tumor tissue. The p60 protein is released by cell death. The detection of pl63 in a body fluid therefore makes it possible to make a statement about proliferative processes and / or that are accompanied by cell death, for example inflammatory processes, in a body. The detection of the pl63 protein can be carried out by specific binding to labeled substances. To these substances that bind -specifically belong the protein p27, the Ran protein and antibodies, generated for example by immunization of animals with the protein pl63 or with partial sequences of this protein. However, detection of the pl63 mRNA in a cell or in a tissue can also be effected by hybridization of the nucleic acid sequence, which encodes the p63 protein, with the corresponding mRNA. An elevation of the sensitivity of this detection is possible through the technology of "polymerase chain reaction" [= Polymerase Chain Reaction (PCR)], in which a few copies of a nucleic acid sequence that has been detected can be multiplied with the help of so-called pairs of primers. Examples of primer pairs for multiplication and for the detection of the nucleic acid sequence encoding pl63 are shown in Tables 12a, b and c. The detection of the RNA encoding the pl63 is however also possible, for example, with the fluorescence of hybridization in si tu published by Gussoni et al., In Nature Biotechnol. 14, 1. 012 (1996). Accordingly, the object of the invention is the detection of a nucleic acid sequence encoding pl63, or of the pl63 protein, for the determination of the proliferation state of a cell or of a tissue, or for the detection of proliferative modifications or they are accompanied by cell death in a living mammal. 8) Particularities of expression systems, which are controlled by pl63, p27 or the pl63 and p27 complex 8. 1. Component b) 8. 1.1. Binding sequence for pl63, p27 or protein complex p63 and p27 [component 2)] In a preferred embodiment of the invention, the expression system contains with its component b2) at least : r.a nucleic acid sequence for the pl63 protein or for part of the p63 protein, which binds to the p27 protein. In another preferred embodiment, the expression system contains with its component b2) at least one sequence of "nucleic acid for an antibody or for a part of an antibody with the binding sequences (VH and VL) for the binding site of the p27 protein for the pl63 protein, or - - for the binding site of the p63 protein for the p27.? n these embodiments, eg the free p27 protein or the protein free p63, present in the cell, binds to the expression product of component b2) and thereby inhibits the transcription factor encoded by component b) and thereby blocks the expression system, however, if for example in a cell the p27 protein is complexed with the pl63 protein, the expression product of the component b2) remains free and consequently the transcription factor (component b)] and the expression system is able to function.These expression systems according to the invention are by c next they are able to function in cells that are dividing (there are presence of complexes of p63 and p27) and are inhibited in resting cells (there is p27 free). In another special form of realization, the expression system contains with its component b2) contains at least one nucleic acid sequence for an antibody or a part of an antibody with the binding sequences (VH and VL) for the p27 and pl63 complex. In this embodiment, the p27 and pl63 complexes bind to the expression product of component b2) and thereby block the expression system, while the free p27 or pl63 does not bind to the expression product of component b). This expression system according to the invention is therefore blocked in cells that are dividing (there is presence of complexes of p63 and p27) and is capable of functioning in resting cells (there is free p27). In the case of the choice of an antibody for a component b2), the portions of the FVLFVH antibody (which bind to epitopes, in the case of a murine origin in a humanized form) are preferably used. Winter and collaborators (Nature 349, 203 (1991)) and by Hoogembooms et al. (Rev. Tr.

Transfus. Hemobiol. 36, 19 (1993)). Antibody fragments are produced correspondingly to the state of the art, for example in the manner described by Winter et al., In Na ture 349, 293 (1991), Hoogenbooms et al., In Rev. Tr. Transfus. Hemobiol. 36_, 19 (1993), Girol. Mol. Immunol. 28., 1-37 (1991) or by Huston et al., Jnt. Rev. Immunol 10_, 195 (1993). A detailed description of the production of antibodies, antibody fragments and recombinant antibody fragments was carried out in the German patent application DE 9649645.4. Fragments of recombinant antibodies are produced directly from existing hybridomas or are isolated with the help of "phage display" technology from libraries of murine or human antibody fragments (Winter et al.

Annu. Rev. Immunol. 12, 433 (1994)). These antibody fragments are then used in the genetic plane directly for coupling with the components b-j_) and b3). For the production of re-combining antibody fragments from hybridomas, the genetic information encoding the antigen-binding domains (JJ, V of the antibodies, by isolation of the mRNA, the reverse transcription of the RNA into cDNA and the subsequent amplification by polymerase chain reaction and the oligonucleotides complete with the 5 'or 3' ends of the variable fragments. The DNA fragments thus obtained, which encode the V ^ and L fragments, are then cloned into bacterial expression vectors and can thus be expressed as p. ex. Fv fragments, single chain Fv fragments (= scFv) or Fab fragments. New antibody fragments can be isolated by means of "phage display" technology also directly from antibody libraries (immunoblots, inexperienced libraries) of murine or human origin. In the "phage display" of antibody fragments, the antigen binding domains are cloned as fusion proteins with the sjP envelope protein gene of filamentous bacteriophages either in the genome of fagcs and in phagemid vectors in gene form of scFv fragments or as Fab fragment genes. The phages that bind to antigens are selected in plastic containers filled with antigens (panning), in paramagnetic "globules", conjugated with antigens, or by binding to cell surfaces. Immunological libraries are produced by PCR amplification of the genes of the variable fragments of antibodies from B lymphocytes of animals or immunized patients. For this, combinations of oligonucleotides are used, which are specific for murine or human immunoglobulins or for the families of human immunoglobulin genes. With the use of non-immunized donors as a source of immunoglobulin genes, "inexperienced" libraries can be produced [naives]. Alternatively, germline genes can be used for the production of semisynthetic antibody repertoires, complementarity determining region 3, of the variable fragments being complemented by PCR with the aid of degenerate primers. These so-called "single pot" libraries have an advantage over immunological libraries that fragments of antibodies against a large number of antigens can be isolated from a single library.

The affinity of the antibody fragments can be further increased by the "visualization of: a ~ cs" technology, producing new libraries of existing antibody fragments by random mutations, codon-based or deliberate, by "chain shuffling" "[chain shuffling] of individual domains with fragments from" inexperienced "repertoires or using bacterial mimic strains, and isolating by refurbished selection under strict conditions fragments of antibodies that exhibit improved properties. Additionally, fragments of Murinc's murine antibodies can be humanized by gradual exchange of one of the variable domains by a human repertoire and subsequent selection with the original antigen ("guided selection"). Alternatively, the humanization of murine antibodies is effected by target-directed exchange of the hypervariable regions of human antibodies by the corresponding regions of the original murine antibody. 8. 1.2. The activation domain [component b-j_)] and the DNA binding domain [component b3)] In the sense of the invention, all available genes of activation domains and DNA binding domains of a transcription factor can be used for component b). Examples of them, whose description should not however limit the invention, are: Activation domains [component b- ^)] at least one cDNA sequence for the transactivation domain (TAD, from TransAktivierungsDománe) HSV1-VP16 acid (amino acids 406 to 488; Triezenberg et al., Genes Developm. 2: 718 (1988), Triezenberg, Curr Opin Developm 5: 190 (1995), or amino acids 413 to 490, Regier et al., Proc. Nati. Acad.

Sci. USA 90, 883 (1993)) or the activation domain of Oct-2 (amino acids 438 to 479; Tanaka et al Mol. Cell. Biol. 14: 6. 046 (1994) or amino acids 3 to 154; Das et al., Nature 374: 657 (1995)) or the activation domain of SP1 (amino acids 340 to 485, Courey and Tijan, Cell 55, 887 (1988)) or the activation domain of NFY (amino acids 1 up to 233, Li et al, J. Biol, Chem. 267, 8,984 (1992), van Hujisduijnen et al., EMBO, J. 9_, 3. 119 (1990); Si? Ha and collaborators, J. Biol. Chem. 92, 1624 (1995); Coustry et al., J. Biol.

Chem. 270, 468 (1995)) or of the activation domain of ITF2 (amino acids 2 to 452; Seipel et al., EMBO J. 13 4.961 (1992)) or of the activation domain of c-Myc (amino acids 1 to 262; Eilers et al.) Or the activation domain of CTF (amino acids 399 to 499; Mermod et al., Cell 58_, 741 (1989); Das and Kerr, Nature 3 A, 657 (1995)) DNA binding domains [component b3)] a cDNA sequence for the DNA binding domain of the Gal4 protein (amino acids 1 to 147; Chasman and Kornberg, Mol. Cell. Biol. 10: 2916 (1990)) or of the LexA protein (amino acids 1 to 81; Kim et al., Science 255: 203 (1992), or the entire LexA protein (amino acids 1 to 202; Brent et al., Cell 43, 729 (1985)) or the lac repressor protein (lac I) (Brown et al., Cell 49: 603 (1987); Fuerst et al., PNAS USA 86: 2549 (1989)) or the tetracycline repressor protein. (tet-R) (Gossen et al., PNAS USA 89; 5. 547 (1992); Din ermann et al., EMBO J. 11: 1. 487 (1992)) or of the ZFHD1 protein (Pomerantz et al.

Science 267: 93 (1995)). It is advantageous in the sense of the invention to attach a nuclear localization signal (NLS) to the 3 'end of the DNA binding domain. 8. 2. Activation sequence activatable by component b) promoter unit II [component c)]. The choice of this activation sequence is adjusted to the choice of tLel DNA binding domain [component b3)] in the gene for a transcription factor [component b)]. For the examples that are exposed in 8.1.2. For DNA binding domains there are, for example, the following possibilities: 8. 2.1. Possibility A) - an activation sequence with at least one binding sequence [nucleotide sequence: 5 '-CGGACAACTGTTGACCG-3', SEQ ID NO .: 1] for the Gal4 protein (Chasman and Kornberg, Mol. Cell. Biol. 10, 2 916 (1990)) and (attached to its 3 'end) the SV40 basal promoter (nucleic acids 48 to 5191; Tooze (compiler), DNA Tumor Viruses (Cold Spring Harbor New York, New York, Cold Spring Harbor Labora tory) or the c-fos promoter (Das et al., Nature 374, 657 (1995)) or the U2 sn RNA promoter or the HSV TK promoter (Papavassiliou et al., J., Biol. Chem. 265. 9402 (1990), Park et al., Molec. Endocrinol., 7, 319 (1993 )) 8. 2.2. Possibility B) - an activation sequence with at least one binding sequence [sequence of 5'nucleotides -TACTGTATGTACATACAGTA-3 ', SEQ ID NO. : 2] for the LexA protein [LexA operator; Brent et al., Na ture 512, 312 (1984)] and (attached to its 1 'end) the SV40 basal promoter (48 nucleic acids up to 5191; Tooze (compiler), DNA Tumor Viruses (Cold Spring Harbor New York, New York, Cold Spring Harbor Labora tory) or other promoter (see Possibility A). 8. 2.3. Possibility C) - an activation sequence • with at least one link sequence to the lac operator (5 'nucleotide sequence -GAATTGTGAGCGCTCACAATTC-3' SEQ ID NO: 3) for the lac repressor protein I (Fuers et al, PNAS USA 86, 2, 549 (1989); Simons et al., PNAS USA 81, 1. 624 (1984)) and (attached to its 3 'end) the SV40 basal promoter (nucleic acids 48 to 5,191); Tooze (compiler), DNA Tumor Viruses (Cold Spring Harbor New York, New York, N. Y., Cold Spring Harbor Laboratory) or another developer (see Possibility A). 8. 2.4. Possibility D) - an activation sequence with at least one tetracycline operator binding sequence (tet O) (nucleotide sequence: 5'-TCGAGTTTACCACTCCCTATCAGTGATAGAGAAAAGTGAAAG-3 ', SEQ ID NO: 4) for the tetracycline repressor protein (tet R) and (attached to its 3 'end) the SV40 basal promoter (nucleic acids 48 to 5191; Tooze (compiler) DNA Tumor Viruses (Cold Spring Harbor New York, N.Y., Cold Spring Harbor Labora tory) or other promoter see Possibility A) 8. 2.5. Possibility E) - an activation sequence with at least one binding sequence [nucleotide sequence 5 '-TAATGATGGGCG-3', SEQ ID NO .: 5] for the ZFHD-1 protein (Pomerantz et al., Science 267, 93 (1995)) and (attached to its 3 'end) - the SV40 basal promoter (nucleic acids 48 to 5191; Tooze (compiler) DNA Tumor Viruses (Cold Spring Harbor New York, N.Y., Cold Spring Harbor Laboratory) or another promoter (see Possibility A). 8. 3. The activation sequence I [component a)]. In the sense of the invention, the nucleotide sequences which, after the binding of transcription factors, activate the transcription of a gene located contiguously to the 3 'end have to be used as activation sequences. The choice of the activation sequence is adjusted to the disease to be treated and to the target cell to be transduced. Thus, the activation sequence [component a)] can be unlimitedly activated, specifically for target cells, in certain metabolic conditions, specifically for a cell cycle or specifically for a virus. A detailed description of these promoter sequences was already carried out in the European patent applications EP95930524.4, EP95931933.6, EP-9? 931204.2, EP95931205.9, EP97101507.8, EP97102547.3, and German DE196.39103.2 and DE196 .51443.6. The sequences of promoters that can be selected belong, for example: 8. 3.1. promoters and promoter sequences, unlimitedly activatable such as for example - the RNA polymerase III promoter - the RNA polymerase II promoter - the CMV promoter and enhancer - the SV40 promoter. 8. 3.2. Sequences of viral promoters and activators such as for example - HBV-HCV-HSV-HPV-EBV-HTLV-HIV In case of using the HIV promoter, the entire LTR sequence must be used, including the TAR sequence [positions from -453 to -80, Rosen et al., Cell 41 813 (1985)] as a virus-specific promoter. 8. 3.3. Metabolically activatable promoter and enhancer sequences such as, for example, hypoxia-inducible enhancers. 8. 3.4. Promoters that can be specifically activated for cell cycles These are, for example, the promoter of the cdc25C gene, the cyclin A gene, the cdc2 gene, the B-myb gene, the DHFR gene, the E2F-1 gene, the cdc25b gene, or also binding sequences for transcription factors that appear or are activated during cell proliferation.

To these binding sequences belong for example the binding sequences for c-myc proteins. Among these binding sequences, monomers or multimers of the nucleotide sequence designated as "Myc E box" must be counted.

[Myc E-Box] [5 '-GGAAGCAGACCACGTGGTCTGCTTCC-3', SEQ ID NO .: 6; Blackwood and Eisenmann, Science 251: 1 .211 (1991)]. 8. 3.5. Promoters activable by tetracycline, such as for example the tetracycline operator in combination with a corresponding repressor 8. 3.6. Chimeric Promoters A chimeric promoter constitutes the combination of an upstream activator sequence, cell-specific activable, metabolically or specifically for viruses, with a downstream promoter module, containing the nucleotide sequence CDE-CHR or E2FBS-CHR, to which suppressor proteins bind, which can thereby inhibit activation of the upstream activator sequence in the GQ and G-j_ phases of the cell cycle (PCT / GB9417366.3; Lucibello et al. , EMBO J. 14, 12 (1994)). 8. 3.7. Promoters that can be activated specifically for cells Among these are preferably promoters or promoter sequences based on promoters or enhancers of such genes, which encode proteins preferably formed within selected cells.

For example, in the sense of the invention, promoters for the following proteins should preferably be used in the following cells: 8. 3.7.1. Sequences of promoters and activators, activated in endothelial cells endothelial glucose-1 transporter, specific for the brain, endogli a -receptor of VEGF-1 (flt-1) receptor of VEGF-2 (flk-1, KDR) tie-1 ot? e-2 receptor of? 61 receptor Eck) B61 - endotelma, especially endothelin B or endothelin endothelin receptors, especially the receptor endothelin B receptors of mannose-6-phosphate von Willebrand factor - IL-lQ, IL -β, receptor of IL-1 vascular cell adhesion molecule (VCAM-1) synthetic sequences of activators As an alternative to natural promoters, specific for endothelial cells, synthetic sequences of activators can also be used, which consist of sites of oligomerized binding agents for transcription factors, which are preferentially or selectively active in endothelial cells. An example of this is the transcription factor GATA-2, whose binding site in the endothelin-1 gene is 5'-TTATCT-3 'is [Lee et al., Biol. Chem. 266, 16. 188 (1991), Dor ann et al., J. Biol. Chem. 267, 1 . 279 (1992) and Wilson et al., Mol. Cell Biol. 10., Four . 854 (1990)]. 8. 3.7.2. Sequences of promoters and activators, activated in cells in proximity with activated endothelial cells - VEGF The gene regulatory sequences for the VEGF gene are the 5 'flanking region, the 3' flanking region, the c-Src gene or the v-Src gene Steroid hormone receptors and their promoter elements (Truss and Beato, Endocr. Rev. 14, 459 (1993)), especially the mouse breast tumor virus promoter. 8. 3.7.3. Promoter and activator sequences, activated in muscle cells, especially in smooth muscle cells - tropomyosin-to-actin, - a-myosin, - receptor for PDGF - receptor for FGF - MRF-4 - phosphofructokinase A - phosphoglyceratomutase - troponin C - myogenin - receptors for endothelin A - desmin - VEGF The gene regulatory sequences for the VEGF gene have already been discussed in the paragraph "Sequences of activated promoters in cells in close proximity to activated endothelial cells" (see above) - artificial promoters "Factors of the Helix-Loop-Helix family (HLH =" helix-loop-helix ") (MyoD, Myf-5, myogens, MRF4) have been - - -. described as specific transcription factors for muscles. In addition, the "zinc finger protein" GATA-4 belongs to the muscle-specific transcription factors. HLH proteins as well as GATA-4 manifest a muscle-specific transcription not only with gene-specific gene promoters, but also in the heterologous context, as well, also with artificial promoters. Such artificial promoters are for example multiple copies of the binding site (to DNA) for muscle-specific HLH proteins, such as box E (MyoD) (eg 4x AGCAGGTGTTGGGAGGC, SEQ ID NO: 7) or multiple copies of the DNA binding site for GATA-4 of the a-myosin heavy chain gene (s-Myosin-Heavy -Chain (eg: 5 '-GGCCGATGGGCAGATAGAGGGGGCCGATGGGCAGATAGAGG-3', SEQ ID NO .: 8) 8. 3.7.4. Sequences of promoters and activators, activated in glial cells These include, in particular, the regulatory sequences of genes or elements derived from genes encoding the following proteins, for example: - the Schwann cell-specific protein, periaxin, - Glutamine synthetase, - the specific protein for glial cells (Glial fibrillary acid protein = GFAP) - the protein of glial cells SlOOb - IL-6 (CNTF) - receptors of 5HT - TNF a, - IL-10 - receptors I and II of the insulin-like growth factor - VEGF. The gene regulatory sequences for the VEGF gene have already been discussed previously. 8. 3.7.5. Sequences of promoters and activators, activated in blood-forming cells To such gene-regulatory sequences belong promoter sequences for genes of a cytokine or its receptor, which are expressed in blood-forming cells or in neighboring cells, such as for example those of the stroma.

These include sequences of promoters for, for example, the following cytokines and their receptors: - stem cell factor receptor (Stem Cell Factor) - stem cell factor - IL-1 - IL-1 receptor - IL-3 - IL-3 receptor (subunit a) - IL-3 receptor (ß subunit) - IL-6 - IL-6 receptor - GM-CSF - GM-CSF receptor (a chain) - interferon regulatory factor 1 ( IRF-1 of Interferon Regulatory Factor 1). The IRF-1 promoter is activated by IL-6 in the same way as by IFN? or IFNß - eptropoietin - erythropoietin receptor. 7. 3.7.6. Sequences of promoters and activators, activated in lymphocytes and / or macrophages These include, for example, the sequences of promoters and activators of the genes for cytokines, cytokine receptors and adhesion molecules as well as receptors for the Fe fragment of antibodies. These include, for example: - IL-1 receptor - IL-la - IL-lß - IL-2 - IL-2 receptor - IL-3 - receptor of 11-3 (subunit: ••) - II receptor - 3 (subunit 3) - IL-4 - receptor of IL-4 - IL-5 - IL-6 - receptor of IL-6 - regulatory factor of interferon-1 (IRF-1). (The IRF-1 promoter is activated by IL-6 in the same way as by IFN, and IFNI-IFNy-responsive promoter-IL-7 ~ J.1 _! - 8 - IL-10-IL-11-IFN? - GM-CSF - GM-CSF receptor (chain a) - IL-13 - LIF - - macrophage colony stimulating factor receptor (M-CSF) - type I and II macrophage purifying receptors - MAC-1 (leukocyte function antigen) - LFA-la (leukocyte function antigen) - pl50.95 (leukocyte function antigen) 8. 3.7.7. Sequences of promoters and activators, activated in synovial cells To these belong the promoter sequences for matrix metalloproteinases (MMP), for example for: - MMP-1 (interstitial collagenase) - MMP-3 (stromelysin / transin). To these belong also the sequences of promoters - for tissue inhibitors of metalloproteinases (TIMP = Tissue Inhibitors of Metalloproteinases), for example - TIMP-l - TIMP-2 - TIMP-3 8. 3.7.8. Sequences of promoters and activators, activated in leukemia cells To these belong, for example, promoters for - c-myc - HSP-70 - bcl-1 / cyclin Dl - bcl-2 - IL-6 - IL-10 - TNFa, TNFβ-HOX-11 - BCR-Abl - E2A-PBX-1 - PML-RARA (retinoic acid-Promyelocytic promyelocytic leukemia receptor Leukemia - Retinole Acid Receptor) - c-myc - the c-myc proteins bind to, and activate, multimers of the nucleotide sequence designated as the Myc-E box (5 '-GGAAGCAGACCACGTGGTCTGCTTCC-3', SEQ ID NO: 6). 8. 3.7.9. Sequences of promoters or activators, activated in tumor cells As a sequence of a promoter or activator, a nucleotide sequence regulating a gene is envisaged, with which transcription factors, formed or active, interact in tumor cells. In the sense of this invention, the regulatory sequences of genes or elements of genes are among the preferred sequences of promoters or activators., which encode especially proteins formed in cancer cells or sarcoma cells. Thus, for example in the case of small cell bronchial carcinomas, the promoter of the N-CAM protein is preferably used, in the case of ovarian carcinomas the promoter of the "Hepatitis growth factor" receptor or plastin L and, in the case of pancreatic carcinomas, the plastin L promoter or the polymorphic epithelial mucin (PEM = Polymorphen Epi thelialen Mucin). 8. 4. The effector gene [component d)] In the sense of the invention, the effector genes [component d)] encode an active substance for the prophylaxis and / or therapy of a disease. Effector genes and promoter sequences are to be selected with respect to the type of disease therapy and taking into account the target cell to be transduced. For example, in the case of the following diseases, the following combinations of promoter sequences and effector genes have to be chosen (a detailed description has already been made in patent applications EP95930524.4, EP95931933.6, EP95931204.2, EP95931205 .9, EP97101507.8, DE196.17851.7, DE196.39103.2 and DE196.51443.6, to which reference is made). 8. 4.1. Tumor therapy 1. 1. Target cells - proliferating endothelial cells or - stromal cells and muscle cells adjacent to endothelial cells or - tumor cells or leukemia cells. • _. '-. - 43 - 1.2 Promoters: - specific for endothelial cells and specific for cell cycles or nonspecific for cells or specific for 5 muscle cells and specific for cell cycles or - specific for tumor cells (solid tumors, leukemias) and specific cell cycles. 1.3. Effector genes for inhibitors of cell proliferation, for example for - the retinoblastoma protein (pRb = pllO) or the pl07 and pl30 related proteins The retinoblastoma protein (pRb = pllO) and the 15 related proteins pl07 and pl30"are deactivated by Phosphorylation The genes of these cell-cycle inhibiting agents, which have mutations for the sites of deactivation of the expressed proteins, should preferably be used. they are harmed in their function. Examples of these mutations were described for pllO. In an analogous manner, the DNA sequence for the pl07 protein or the pl30 protein is mutated. 25 - the p53 protein The p53 protein is deactivated in the cell either by binding to special proteins such as for example MDM2, or by oligomerization of p53 through the dephosphorylated C serine terminal. Preferably, a DNA sequence is used for a p53 protein that is shortened at the C terminus by serine 392 - p21 (WAF-1) - p66 protein 35 - other cdk inhibitors - the GADD45 protein - the protein bak - a binding protein for a regulatory protein (see II. i.) 1. 4. Effector genes for factors that induce coagulation and inhibitors of angiogenesis, for example - the plasminogen activator inhibitor-1 (PAI-1) - PAI -2 - PAI-3 - angistatma - interferenes (IFNa, IFNß or IFN?) - platelet factor 4 (Platelet Factor 4) - TIMP-2 - TIv.F-3 - leukemia inhibitory factor (LIF of Leukemia Inhibi tory Factor) - tissue factor (TF = tissue factor) and its active fragments for coagulation .5. Effector genes for cytostatic and cytotoxic proteins, for example para-perforin-granzyme-IL-2-IL-4-IL-12-interferons, such as for example IFN-a, IFNβ or IFN? - TNFs, such as TNFα or TNFβ-oncostatin M, - sphingomyelinase - magainin and magainin derivatives Effector genes for cytostatic or cytotoxic antibodies and for fusion proteins between antibody fragments that bind antigens with cytostatic, cytotoxic or provocative proteins or enzymes of inflammations - Cytostatic or cytotoxic antibodies belong to those directed against endothelial cell membrane structures, as described for example by Burrows et al. (Pharmac.Ther.64., 155 (1994)), by Hughes et al. (Cancer Res. 49, 6214 (1989)) and by Maruyama et al. (PNAS USA ß7_, 5744 (1990)).

Especially among them are antibodies against VEGF receptors. - Furthermore, they belong to them cytostatic or cytotoxic antibodies directed against membrane structures in tumor cells. Such antibodies were presented compiled, for example, by Sedlacek et al., In Contrib. to Oncol. 32, Karger Verlag, München (1988) and Contrib. to Oncol. 43, Karger Verlag, München (1992). Other examples are antibodies against sialyl Lewis; against peptides in tumors, which are recognized by T cells; against proteins expressed by oncogenes, against gangliosides such as GD3, GD2, GM2, 9-0-acetyl-GD3, fucosyl GM1; against blood group antigens and their precursors; against antigens in the polymorphic epithelial mucin; against antigens in heat shock proteins (fieat Shock Proteins) - also belong to them antibodies directed against membrane structures of leukemia cells. A large number of such monoclonal antibodies have already been described for diagnostic and therapeutic procedures (compilations are found in Kristensen, Danish Medical Bulletin 41, 52 (1994)); .Schranz, Therapia Hungarica 38., 3 (1990); Drexler et al., Leuk. Res. 10, 279 (1986); Naeim, Dis. Markers 7, 1 (1989); Stickney et al., Curr. , Opin. Oncol. 4, 847, 1992); Drexler et al., Blut 57, 327 (1988); Freedman et al., Cancer Invest. 9, 69, 1991)). Depending on the type of leukemia, monoclonal antibodies or their antibody fragments that bind to antigens, directed against the following membrane antigens, are suitable as ligands: Cells Antigens of AML membranes CD1 3 CDl 5 CD33 CAMAL S1aIos1l-Le B-CLL CD5 CD1 c CD23 Idiotypes and isotypes of membrane immunoglobulins T-CLL CD33 M38 Receptors of iL-2 T-cell receptors ALL CALLA CD19 Non-Hodgkin lymphoma - The humanization of murine antibodies, the preparation and optimization of genes for Fab and Fv rec fragments. they are carried out in a manner corresponding to the technique known to those skilled in the art (linte et al., Nature 349, 293 (1991); Hoogenbooms et al., Rev. Tr.

Transfus. Hemobiol. 3 £, 19 1993; Girol. Mol. Immuno 1. 28 1379 (1991) or Huston et al., Intern. Rev.

Immunol. 10., 195 (1993)). The fusion of fragments Recombinant Fv with genes for proteins or cytostatic, cytotoxic or inflammation-provoking enzymes is carried out in the same way according to the state of the art known to those skilled in the art. 1. 7. Effector genes for ligand fusion proteins that bind to target cells with cytostatic and cytotoxic proteins. The ligands include all substances that bind to membrane structures or membrane receptors on endothelial cells. For example belong to them - Cytokines such as for example IL-1 or growth factors, or their fragments or partial sequences thereof, which bind to receptors that are expressed by endothelial cells such as for example PDGF, bFGF, VEGF , TGF. - Also belong to them adhesion molecules, which bind to activated and / or proliferating endothelial cells. They include, for example, SLex, LFA-1, MAC-1, LECAM-1, VLA-4 or vitronectin. - They also belong to them substances that bind to membrane structures or receptors in membranes of tumor cells or leukemias. For example, they include hormones or growth factors or their fragments or partial sequences thereof, which bind to receptors expressed by leukemia cells or tumor cells. Such growth factors have already been described (compilations in Cross et al., Cell 64., 271 (1991), Auli tzky et al., Drugs 48, 667 (1994), Moore, Clin. Cancer Res. 1, 3 (1995), Van Kooten et al., Leuk. Lymph. 12., 27 (1993)). The fusion of the genes of these ligands that bind to the target cell with proteins or cytostatic, cytotoxic or inflammation-provoking enzymes is carried out correspondingly to the state of the art with the methods known to those skilled in the art. 1. 8. Effector genes for inflammation inducers, for example for - IL-1 - IL-2-RANTES (MCP-2) - monocyte activating and chemotactic factor (MCAF = monocyte chemotactic and activating factor) - IL-8 - inflammatory protein of macrophages-1 (MIP-loí, -ß = macrophage inflammatory protein- 1) - neutrophil activating protein-2 (NAP-2 = neutrophil activating protein-2) - IL-3 - IL-5 - human leukemia inhibitory factor (LIF = leukemia inhibitory factor) - IL-7, - IL-11 - IL-13 - GM-CSF - G-CSF - M-CSF - cobra venom factor (CVF = Cobra venom factor) or partial sequences of FVC that functionally correspond to complement factor Human C3b, that is to say that they can bind to complement factor B and that after dissociation by factor D constitute a C3 convertase - human complement factor C3 or its partial sequence C3b - dissociation products of human C3 complement factor , which functionally and structurally resemble FVC - bacterial proteins that activate complement or cause inflammation, such as, for example, Salmonella typhi murium porins, Staphylococcus aureus conglomeration factors, especially Gram m-negative, major outer membrane protein ["Major outer membrane protein"] of Legionellas or of Haemophilus influenzae type B or of Klebsiellas or M molecules of Group G Streptococci.

Effector genes for enzymes for the activation of cytostatic agent precursors, for example for enzymes, which transform or unfold inactive precursor substances (prodrugs) in active cytostatic agents (drugs) Such substances, and the prodrugs and drugs in each case are already relevant. they have been described in a compilation by Deonarain et al. (Br. J. Cancer 70, 786 (1994)), by Mullen (Pharmac. Ther. 199 (1994)) and by Harris et al. (Gene Ther. 1, 170 (1994)). For example, the DNA sequence of one of the following enzymes must be used: - thymidine kinase of the herpes simplex virus - thymidine kinase of the varicella Zoster virus - bacterial nitro-reductase - bacterial ß-glucuronidase - vegetal ß-glucuronidase of Sécale cereale - human ß-glucuronidase - human carboxy-peptidase (CB), for example CB-A of the priming cell or mast cell, CB-B of the pancreas carboxypeptidase or bacterial - bacterial ß-lactamase - bacterial cytosma-deaminase - catalase or human peroxidase - phosphatase, in particular human alkaline phosphatase, human acid prostate phosphatase or acid phosphatase type 5 -oxidase, in particular human lysyl oxidase or D-amino-oxidase human acid - peroxidase, in particular human glutathione peroxidase, human eosinophil peroxidase or human thyroid peroxidase - galactosidase 8. 4.2. Therapy of autoimmune diseases and inflammations 2. 1. Target cells: - proliferating endothelial cells or - macrophages and / or lymphocytes or - synovial cells 2. 2. Promoters: - specific for endothelial cells and specific for cell cycles, or specific for macrophages and / or lymphocytes and / or specific for cell cycles or - specific for synovial cells and / or specific for cell cycles 2. 3. Effector genes for the therapy of allergies, for example for - IFNß - IFN? - IL-10 - antibodies or fragments of antibodies against IL-4 - soluble IL-4 receptors - IL-12 - TGFβ 2. 4. Effector genes for the inhibition of rejection of transplanted organs, for example for - IL-10 - TGFβ - soluble IL-1 receptors - soluble IL-2 receptors - IL-1 receptor antagonists - IL-6 receptors soluble - immunosuppressive antibodies or their fragments containing H and VL or their H and VL fragments bound through a linker. Immunosuppressant antibodies are for example antibodies specific for the T cell receptor or its complex with CD3, against CD4 or CD8, and in addition against the IL-2 receptor, the IL-1 receptor or the IL-4 receptor or against adhesion molecules CD2, LFA-1, CD28 or CD40. 2. 5. Effector genes for the therapy of autoimmune diseases mediated by antibodies, for example for - TGFβ - IFNα - IFNβ - IFN? - IL-12 - soluble IL-4 receptors - soluble IL-6 receptors - immunosuppressive antibodies or their fragments containing VH and Vt_, effector genes for the therapy of cell-mediated autoimmune diseases, for example - IL-6 - IL-9 - IL-10 - IL-13 - TNFa or TNFβ - an immunosuppressive antibody or its fragments containing VH and VL Effector genes for inhibitors of cell proliferation, proteins and cytostatic or cytotoxic enzymes for the activation of cytostatic agent precursors. Examples of genes encoding such proteins have already been pointed out in the paragraph "Effector genes for tumor therapy". In the same way as already described there, effector genes, which encode antibody fusion proteins or Fab fragments or Fv rec fragments, can be used in the sense of the invention. of these antibodies or other ligands specific for the target cell and encode the aforementioned cytokines, growth factors, receptors and proteins and cytostatic and cytotoxic enzymes.

Effector genes for the therapy of arthritis In the sense of the invention, effector genes are chosen, whose expressed protein directly or indirectly inhibits an inflammation, for example in a joint and / or favors the reconstitution of the extracellular matrix (cartilage, connective tissue ) in the joint. To these belong, for example - the IL-1 receptor antagonist (IL-1-RA); IL-1RA inhibits the binding of IL-la, β-the soluble IL-1 receptor; the soluble IL-1 receptor binds and deactivates IL-1 - IL-6; IL-6 increases the secretion of TIMP and superoxides and decreases the secretion of IL-1 and TNFa by synovial cells and chondrocytes - the soluble TNF receptor; the soluble TNF receptor binds and deactivates TNF - IL-4; IL-4 inhibits the formation and secretion of IL-1, TNFa and MMP-IL-10; IL-10 inhibits the formation and secretion of IL-1, TNFa and MMP, and increases the secretion of TIMP-insulin-like growth factor (IGF-1 = Insulin-like Growth Factor); IGF-1 stimulates the synthesis of extracellular matrix - TGFβ, especially TGFβ1 and TGFβ2; TGFβ stimulates the synthesis of extracellular matrix - superoxide dismutase - TIMP, especially TIMP-1, TIMP-2 or TIMP-3.

Therapy of defective formation of blood cells Target cells: - immature cells in proliferation, from the blood formation system or - neighboring stromal cells with blood-forming cells Promoters: - specific for blood forming cells and / or specific for cell cycles - unspecific for cells and specific for cell cycles. 3. 3. Effector genes for anemia therapy, for example for .na 3. 4. Effector genes for the therapy of leukopenia, for example for - G-CSF - GM-CSF - M-CSF 3. 5. Effector genes for the therapy of thrombocytopenia, for example for - IL-3 - leukemia inhibitory factor (LIF) - IL-11 - thrombopoietin 8. 4.4. Therapy of nervous system injuries 4. 1. Target cells: - glia cells or - proliferating endothelial cells 4. 2. Promoters - specific for glia cells and specific for cell cycles or - specific for endothelial cells and specific for cell cycles or - nonspecific for cells and specific for cell cycles 4. 3 Effector genes for neuronal growth factors, for example - FGF - nerve growth factor (NGF = Nerve growth factor) Brain derived neurotrophic factor (BDNF = neurotrophic factor) - neurotrophin-3 (NT-3) - neurotrophin-4 (NT-4) - ciliary neurotrophic factor (CNTF = Ciliary neurotrophic factor) Effector genes for enzymes, for example para-tyrosine hydroxylase-dopa decarboxylase Effector genes for cytokines and their inhibitors, which inhibit or neutralize the neurotoxic effect of TNFOI, for example - TGFβ - soluble TNF receptors TNF receptors neutralize TNFa - IL-10 inhibits IL-10 formation of IFN ?, TNFa, IL-2 and IL-4 - soluble IL-1 receptors - receptor I of IL-1 - receptor II of IL-1 soluble IL-1 receptors neutralize the activity of IL-1 - receptor antagonist IL-1 - soluble IL-6 receptors Therapy of disorders of the coagulation and blood circulation systems target cells: - endoteiiaies cells or - proliferating endothelial cells - somatic cells in the vicinity of endothelial cells and smooth muscle cells or - macrophages . 2. Promoters: - nonspecific for cells and specific for cell cycles - specific for endothelial cells, smooth muscle cells or macrophages and specific for cell cycles . 3. Structural genes for the inhibition of coagulation or for the activation of fibrinolysis, for example for - the tissue plasminogen activator (tPA = Tissue Plasminogen Activator) - - the plasminogen activator of the urokinase type (uPA Urokinase-type Plasminogen Activator) - hybrids of tPA and uPA - protein C - hirudin - inhibitors of serine proteinases (serpins), such as for example the inhibitor C-1S, antitrypsin or antithrombin III - the inhibitor of the tissue factor pathway (TFPI = Tissue Factor Pathway Inhibitor) . 4. Effector genes for the promotion of coagulation, for example for - F VIII - F IX - von Willebrand factor - F XIII - PAI-1 - PAI-2 - tissue factor and fragments thereof Effector genes for angiogenesis factors, for example for - VEGF - FGF Effector genes for lowering blood pressure, for example para-kallikrein-nitric oxide-synthase [= ni tric oxide synthase] endothelial cells Effector genes for the inhibition of smooth muscle cell proliferation after endothelial layer injury, for example for an antiproliferative, cytostatic or cytotoxic protein or an enzyme for the cleavage of cytostatic agent precursors to form cytostatic agents as already it has been indicated above (in the section on "tumors") or - a fusion protein of one of these active substances with a ligand, for example an antibody or antibody fragment that is specific for muscle cells.

Effector genes for other blood plasma proteins, for example para-albumin-inactivator Cl-serum cholinesterase-transferrin-1-antitrypsin Vaccinations Target cells: - muscle cells or - macrophages and / or lymphocytes - endothelial cells Promoters: - nonspecific and specific for cell cycles or - specific for target cells and / or specific for cell cycles Effector genes for the prophylaxis of infectious diseases The possibilities of producing effective vaccines by conventional means are limited. As a result, the technology of DNA vaccines was developed. These DNA vaccines, however, raise questions about the intensity of the effect (Fynan et al., Int. J. Immunopharm. 17, 79 (1995); Donnelly et al., Immunol. 2, (1994)). According to this invention, it is necessary to have a higher activity of DNA vaccines. As an active substance, the DNA of a protein formed by the pathogenic agent of infection must be chosen, which, by provocation of an immunological reaction, that is to say by formation of antibodies and / or by cytotoxic T lymphocytes, leads to neutralization and / or annihilation of the pathogenic agent. Such so-called neutralization antigens are already applied as antigens for vaccines (see compilation in the article by Eliis, Adv. Exp. Med. Biol. 327, 263 (1992)).

Preferred in the sense of the invention are DNA encoding neutralization antigens of the following pathogens: - influenza A virus - HIV [= human immunodeficiency virus] - rabies virus - HSV (herpes simplex virus = Herpes Simplex) Virus) - RSV (respiratory syncytial virus - = Respiratory Syncytial Virus) - parainfluenza virus - rotavirus - VZV (varicella zoster virus = Varicella Zoster Virus) - CMV (cytomegalovirus CytoMegalo -Virus) - measles virus - HPV (human papillomavirus = Human Papilloma Viruses) - HBV (hepatitis B virus) - HCV (hepatitis C virus) - HDV (hepatitis D virus) - HEV (hepatitis E virus) - HAV (hepatitis A virus) - antigen Vibrio Cholera - Borrelia Burgdorferi - Heli cobacter pylori - malaria antigen - However, the DNA of an antiidiotypic antibody or its fragments that bind to antigens, whose antigen-binding structures ( the "complementarity determining regions" complement i and determining regions) constitute copies of the protein or carbohydrate structure of the pathogen neutralizing antigen of infection - such anti-idiotypic antibodies may especially replace the carbohydrate antigens in pathogens of bacterial infections. Such antiidiotypic antibodies and their cleavage products were described compiled by Hawkins et al. (J. Immunother., 14., 273 (1993)) and by Westerink and Apicella (Springer Seminars in Immunopathol 15, 227 (1993)). 6. 4. Effector genes for "tumor vaccines" - To these belong antigens located in tumor cells. Such antigens were represented compiled, for example, by Sedlacek et al., In Contrib. to Oncol. 32., Karger Verlag, München (1988) and Contrib. to Oncol 43_, Karger Verlag, München, 1992). Other examples are the genes for the following protein antigens or for the variable region (VL, VH) of anti-idiotypic antibodies corresponding to the following non-protein antigens: - gangliosides - sialyl-Lewis - peptides in tumors that are recognized by T-proteins expressed by oncogenes - antigens of blood groups and their precursors - antigens in tumor-associated mucin - antigens in heat shock proteins .4.7. The therapy of chronic infectious diseases .1. Target cell: - liver cell - lymphocyte and / or macrophage - epithelial cell - endothelial cell 7. 2. Promoters - specific for viruses or specific for cells and specific for cell cycles 7. 3. Effector genes, for example for - a protein, which has cytostatic, apoptotic or cytotoxic effects. an enzyme, which unfolds a precursor compound of an antiviral or cytotoxic substance to form the active substance. 7. 4. Effector genes for antiviral proteins cytokines and antivirally active growth factors. These include, for example, IFNa, IFNβ, IFNα, TNFβ, TNFα, IL-1 or TGFβ-antibodies with a specificity that deactivates the respective virus or its fragments containing VJJ and VL or its bound VH and V ^ fragments. through a linker, prepared as already described. Antibodies against virus antigens are for example anti HBV anti HCV anti-HSV anti-HPV anti-HIV anti-EBV anti-HTLV anti-Coxsackie virus anti-Hantaan virus - a protein that binds to Rev. These proteins bind to Rev RNA and inhibit retroviral genes expression in later stages of transcription, dependent on Rev. Examples of proteins that bind to Rev are: RBP9-27 RBP1-8U RBP1-8D pseudogenes of RBP1-8 - ribozymes that digest gene mRNAs for proteins for cell cycle control or virus mRNAs. Catalytic ribozymes for HIV were described compiled, for example, by Christoffersen et al., J. Med. Chem. 38. 2033 (1995) 7. 5. Effector genes for antibacterial proteins Antibacterial proteins belong, for example, to antibodies, which neutralize bacterial toxins or opsonize bacteria. They belong, for example, to antibodies against Meningococcus C or B E. coli Borrelia Pseudomonas Helicobacter pylori and Staphylococcus aureus 8. 5. Combination of the same or different effector genes The object of the invention is also a self-reinforcing expression system, possibly controlled by pharmacological means, in which a combination of the DNA sequences of two identical effector genes or of two different effector genes is presented [ components d) and d1)]. For the expression of both DNA sequences, another promoter sequence, or preferably the cDNA of an "entry site for internal ribosomes" (internal ribosome entry si te = IRES) as a regulatory element between both effector genes. An IRES makes possible the expression of two DNA sequences linked together through an IRES.

Such IRES were described for example by Montford and Smith (TIG 11, 179 (1995)); Kaufman and collaborators. Nucí Acids Res. 19, 4. 485 (1991); Morgan and collaborators, Nucí.

Acids Res. 20 .. 1293 (1992); Dirks et al., Gene 128, 247 (1993); Pelletier and Sonenberg, Nature 334, 320 (1988); and Sugitomo et al., BioTechn. 12, 694 (1994)). Thus, for example, the cDNA of the Poliovirus IRES sequence can be used (positions <140 to> 630 of the 5 'UTR). Preferably, in the sense of the invention, effector genes having an additive effect are to be linked through other promoter sequences or an IRES sequence. In the meaning of the invention, preferred combinations of effector genes are, for example, 8. 5.1. the therapy of tumors - identical or different proteins, cytostatic, apoptotic, cytotoxic or excitatory of inflammations or - same or different enzymes for the unfolding of the precursor compound of a cytostatic agent 8. 5.2. the therapy of autoimmune diseases - cytokines or different receptors with synergistic effect for the inhibition of the cellular and / or humoral immunological reaction or - TIMP 's different or equal 8. 5.3. the therapy of the defective formation of blood cells - different cytokines that occur hierarchically, such as for example IL-1, IL-3, IL-6 or GM-CSF and erythropoietin, GCSF or thrombopoietin 8.5.4. nerve cell injury therapy - a neuronal growth factor and a cytokine or the inhibitor of a ctcquma, 8. 5.5 the therapy of disorders of the blood coagulation system and blood circulation - an antithrombotic agent and a fibrinolytic agent (eg tPA or uPA) or - a cytostatic, apoptotic or cytotoxic protein, and an antithrombotic agent or agent fibrinolytic - several different blood coagulation factors, acting synergistically, for example FVIII and vWF or F VIII and F IX 8. 5.6. Vaccinations - an antigen and an immunostimulatory cytokine, such as for example a receptor for IL-la, IL-lß, IL-2, GM-CSF, IL-3 or IL-4 - different antigens of an infectious or infectious agent different pathogens of infections or different antigens of a tumor type or of different types of tumors. ~~ 8. 5.7. Therapy of viral infectious diseases - an antiviral protein and a cytostatic, apoptotic or cytotoxic protein - antibodies against different surface antigens of a virus or of several viruses. 8. 5.8. Therapy of bacterial infectious diseases - antibodies against different surface antigens and / or toxins of a germ 8.6. Introduction of signal sequences and transmembrane domains 8. 6.1. Reinforcement of the translation For the reinforcement of the translation it is possible to introduce, at the 3 'end of the promoter sequence and immediately next to the 5' end of the initiation signal (ATG) of the signal or transmembrane sequence, the sequence of GCCACC or GCCGCC nucleotides (Kozak, J. Cell Biol. 108, 299 (1989)). 8. 6.2. Facilitation of secretion To facilitate the secretion of the effector gene expression product, the homologous signal sequence contained in the DNA sequence of the effector gene can be replaced by a heterologous signal sequence, which enhances extracellular secretion. Thus, for example, the signal sequence for the immunoglobulin can be introduced (position in the DNA <63 to> 107; Riechmann et al., Nature, 332, 323 (1988)) or the signal sequence for the CEA ( position in DNA = 33 up to> 134; Schrewe et al., Mol. Cell. Biol. 10, 2. 738 (1990); Berling et al., Cancer Res. 50, 6.534 (1990)) or the signal sequence of the human respiratory syncytial virus glycoprotein (cDNA of the amino acids <38 to = 50 or 48 to 65; Lichtenstein et al., J.

Gen Virol. 77, 109 (1996)). 8. 6.3. Anchoring of the active substance 3. 1) For the anchoring of the active substance in the cell membrane of the transduced cell, which forms the active substance, a sequence for a transmembrane domain can be introduced alternatively or additionally to the signal sequence. Thus, for example, the transmembrane sequence of the human macrophage colony stimulating factor can be introduced (position in the DNA = 1485 to = 1554, Cosman et al, Behring Inst. Mitt. 83., 15 (1988) or the sequence of DNA for the signal and transmembrane region of the glycoprotein G of the respiratory syncytial virus (RSV = Respiratory Syncytial Virus) human (amino acids 1 to 63. or their partial sequences, amino acids 38 to 63; Vij aya and collaborators, Mol. Cell. Biol. 8, 1.709 (1988); Lichtenstein et al., J. Gen. Virol 77, 109 (1996) or the ADX sequence for the signal and transmembrane region of influenza virus neuramimdase (amino acids 7 to 35 or the partial sequence of amino acids 7 to 27; Brown et al., J. Virol 62 3824 (1988)) between the promoter sequence and the sequence of the effector gene. 3. 2) For the anchoring of the active substance in the cell membrane of the transduced cells forming the active substance, however, the nucleotide sequence for a glycophosphoi-lipid anchor can also be introduced. The introduction of a glycophospholipid anchor is carried out at the 3 'end of the nucleotide sequence for the effector gene and can be carried out in addition to the introduction of a signal sequence. Glycophospholipid anchors have been described, for example, for CEA, for N-CAM and for other membrane proteins, such as for example Thy-1 (see compilation in Ferguson et al., Ann.Rev. Biochem. 57_, 285 (1988)). 3. 3) Another possibility of anchoring active substances to the cell membrane corresponding to the present invention is the use of a DNA sequence for a fusion protein of a ligand and an active substance. The ligand specificity of this fusion protein is directed towards a membrane structure located in the cell membrane of the target cell chosen. The ligands, which bind to the cell surface, belong, for example, antibodies or fragments of antibodies, directed against structures on the surface, for example, of endothelial cells. They are especially counted among them antibodies against the VEGF receptors or against quinine receptors - or muscle cells, such as antibodies against actin or antibody or antibodies against angiotensin II receptors or antibodies against receptors for growth factors, such as for example against EGF receptors or against PDGF receptors or against FGF receptors or antibodies against endothelin A-A receptors. The ligands also include antibodies or fragments thereof, which are directed against tumor-specific antigens or associated with tumors located in the cell membrane of tumors Such antibodies have already been described. The murine monoclonal antibodies are preferably used in a humanized form. Fab and Fv fragments rec. and their fusion products are produced, as already described, with the technology known to a person skilled in the art. The ligands also include all the active substances, for example cytokines or adhesion molecules, growth factors or their fragments or partial sequences of them, mediators or peptide hormones, which bind to membrane structures or membrane receptors located in the respective chosen cell. For example they belong to them - ligands for endothelial cells, such as IL-1, PDGF, bFGF, VEGF, TGGβ or quinine and derivatives or quinine-like compounds - they also belong to them adhesion molecules. Such adhesion molecules as for example SLex, LFA-1, MAC-1, LeCAM-1, VLA-4 or vitronectin or derivatives or compounds analogous to vitronectin, have already been described for endothelial cells (compilations in Augustin-Voss et al. J. "Cell. Biol. 119, 483 (1992); Pauli et al.

Cancer Metast. Rev. 9, 175 (1990); Honn et al., Cancer Metast. Rev. 11, 353 (1992); Varner and collaborators, Cell. Adh. Commun. 3, 367 (1995)).

Legend of the figure Figure 1: Artificial nucleic acid structure according to the invention Table 1 Molecule Domain DNA binding activity involved I galactosidase (Gal) + p27 (1-198) - - + p27 (1-198) - + + p27 (1-198) p163 + + - p163 + + Myc 262-439 p163 + + Max p163 + Protimosima p163 + + LAZ3 / Bcl6 p163 + + p27 (1-178) p163 + + + + + p27 (1-94) p163 + + + p27 (69-198) p163 + + + + + p27 (69-94) p163 + nd + p27 (1-198) p163 (121-252) + + + + Table 2 Application to the binding column to the affinity chromatography column coated with fusion protein Glutathione-glutathione-trans erasa-p1 63 transferase p27 (marked with: 'S) + recombinant + + + Cellular extract (RAT 1 -Myc ER) (+) containing p27 Cellular extract (RAT 1 -Myc ER), + + + containing p27 (heated at 95 ° C for 2 min) cd -2 (cellular extract) cdk-4 (cellular extract) Table 3: [SEQ ID NO .: 9.}.

TCGAATTGGG TACCGGGCCC CCCCTCGAGG TCGACCGTAT CGATAAGCTT GATATCGAAT 60 TCGCGGCCGC TCGAGTTACA AGATGGCGGC CCCGGGCGCT CTCTTCACCG TTCTGTAGCA 120 GCTTCGGGCT GAGCGGATGT CTCTTCTTGT CCTCAGTGTC GGACTCAGAG ACACACGGCT 180 CCCGAGTTCT GCTGATCACG AAGTTCCCGG AGGCGCTCGA CGCACCGGAA TCTCCCAGCG 240 GCCGCGACCG CCGCCTCGGC CCTGCTCGCC GCGGCGCCGG GACTCCAGCG TGATCGGCGG 300 CGGCAGTCAA GGTTCACAAA AATGGCGAAG AGAGTTGCGG AGAAGGAGTT GACTGACAGG 360 AACTGGGATG AGGAAGACGA AGTTGAAGAG ATGGGAACAT TCTCAGTGGC CAGTGAGGAA 420 GTCATGAAGA ACAGAGCCGT AAAGAAGGCA AAGCGCAGAA ACGTTGGATT TGAATCTGAT 480 AGCGGAGGAG CCTTTAAAGG TTTCAAAGGT TTGGTTGTGC CTTCTGGAGG AGGAGGGTTT 540 TCTGGATTTG GTGGCTCTGG AGGAAAGCCT CTGGAAGGAC TGACAAATGG AAACAGCACA 600 GACAATGCCA CGCCCTTCTC CAATGTAAAG ACAGCAGCAG AGCCCAAGGC AGCCTTTGGT 660 TCTTTTGCTG TGAATGGCCC TACTACCTTG GTGGATAAAG TTTCAAATCC AAAAACTAAT 720 GGGGACAGCA ATCAGCCGCC CTCCTCCGGC CCTGCTTCCA GTACCGCCTG CCCTGGGAAT 780 GCCTATCACA ASCAGCTGGC TGGCTTGAAC TGCTCCGTCC GCGATTGGAT AGTGAAGCAC 840 GTGAACACAA ACCCGCTTTG TGACCTGACT CCCATTTTTA AAGACTATGA GAGATACTTG 900 GCGACGATCG AGAAGCAGCT TGAGAATGGA GGCGGCAGCA GTTCTGAGAG CCAGACAGAC 960 AGGGCGACGG CTGGAATGGA GCCTCCTTCC CTTTTTGGTT CAACAAAACT ACAGCAAGAG 1020 TCACCATTTT CATTTCATGG CAACAAAGCG GAGGACACAT CTGAAAAGGT GGAGTTTACA 1080 GCAGAAAAGA AATCGGACGC AGCACAAGGA GCAACAAGTG CCTCGTTTAG TTTCGGCAAG 1140 AAAATTGAGA GCTCGGCTTT GGGCTCGTTA AGCTCTGGCT CCCTAACTGG GTTTTCATTC 1200 TCTGCTGGAA GCTCCAGCTT GTTTGGTAAA GATGCTGCCC AGAGTAAAGC AGCCTCTTCG 1260 CTGTTCTCTG CTAAAGCATC CGAGAGTCCG GCAGGAGGCG GCAGCAGCGA GTGCAGAGAT 1320 GGTGAAGAAG AGGAGAATGA CGAGCCACCC AAGGTAGTGG TGACCGAAGT AAAGGAAGAG 1380 GATGCTTTCT ACTCCAAAAA ATGTAAACTA TTTTACAAGA AAGACAACGA ATTTAAAGAG 1440 AAGGGTGTGG GGACCCTGCA TTTAAAACCC ACAGCAACTC AGAAGACCCA GCTCTTGGTG 1500 CGGGCAGACA CCAACCTAGG CAACATACTG CTGAATGTTC TGATCGCCCC CAACATGCCG 1560 TGCACCCGGA CAGGAAAGAA CAACGTCCTT ATCGTCTGTG TCCCCAACCC CCCACTCGAT 1620 GAGAAGCAGC CCACTCTCCC GGCCACCATG CTGATCCGGG TGAAGACGAG CGAGGATGCC 1680 GATGAATTGC ACAAGATTTT ACTGGAGAAA AAGGATGCCT GAGCACTGAG GCTGACCAAG 1740 GCATGTTGCC ACGTTGCTGC TTCCCCTCCG TCCCTAACTT AGTCACATTC TTTCCTCTTC 1800 TACTGTGACA TTCTGAGAAC TTCTAGGTAA CTTGAACTTT TGTGAGGAAG ATTAAGGCCA 1860 ATAAATCCTT TCAGTGGCGG CCGCGAATTC CTGCAGCCCG GGGGATCCAC TAGTTCTAGA 1920 GCGGCCGCCA CCGCGGTGGA GCTCCAGCTT TTGGGAGA 1958 Table 4: pl63: 1 MAKRVAEKELTDRNWDEEDEVEEM 24 [SEQ ID NO .: 10] MAKRVA + ++ + D + +++ YNup2 1 MAKRVADAQIQRETYDSNESDDDV 24 [SEQ ID NO .: 11] P163: 137 NQPPSSGPASSTACPGNAYHKQIAGLNCS N + + G A P + + L LN YNup2: 71 NRADGTGEAQVDNSPTTESNSRLKALNLQ VRDWIVKHVNTNPLCDLTPIFKDYERYLATI 196 [SEQ ID NO .: 12] ++ + V PL DL P + F YE Y + I FKAKVDDLVLGKPLADLRPLFTRYELYIKNI 130 [SEQ ID NO .: 13] P163: 215 ATAGMEPPSLFGSTKLQQESPFSFHGNKAEDT A + P ST + PF G ++ YNup2: 535 ANSSTSPAPSIPSTGFKFSLPFEQKGSQTTTN SEKVEFTAEKKSDAAQGAT 265 [SEQ ID NO .: 14] K E T E + + Q AT DSKEESTTEATGNESQDAT 585 [SEQ ID NO .: 15] P163: 239 HGNKAEDTSEKVEFTAEKKSDAAQGATSASFSFG 272 [SEQ ID NO .: 16] + G ++++ D + + + A + + AT + FSFG YNup2: 444 NGSESKDSDKPSLPSAVDGENDKKEATKPAFSFG 477 [SEQ ID NO .: 17] P163: 399 LGNIIÍNVLIAPNMPCTRTGKNNVI.IVCVPNPPLDEKQPT 438 [SEQ ID NO .: 18] + GN + LLN + + N ++ P D K T YNup2: 655 MGNVX-LNATVVDSFKYEPIAPGNDNLIKAPTVAADGK-.VT 694 [SEQ ID NO .: 19] Table 5 RBPl (Mouse) 5 DSHADHÜTST ENADESTTHP - QFEESVSVPE RBP1 (Human) 5 DSHADHQTST ENADESNHDP - QFEEIVSVPE NÜP2p (Yeast) 560 SQTTTNI1SKE ESTT ATGNESQDATKSTOATPBBSKP P163 (Mouse) 307 QSKAASSLFSAKASESPAGGGSSECRDGEEEENDEPPKV ? RBPl (Mouse) QEI tr, EEDEKCT.raMga-CTJFRFAfiKtmt.P * ^^ RBPl (Human) QElKTLEEDEEE KlíRAKLER-iOSENDLPEHKERßTsDVEtL HK-NUP2p (Yeast) INLQNGEEDEVALFSQKAKLMTENA - ETKSYDSRGVGEMKLLKKKD PL63 (Mouse) WTEVK - EEDAFYSKKCKLEYKKDNE KEKSVßTLH -ia > T- ! RBP1 (Mouse) -C EKGTIBIilfllRDKTIj ANHYITPMMELKP-NAGSDRA V NTHTD RBPl (Human) EKGTIRIiMRRDKTIj -CA "HYITPMMEia-P - mGSDRA V NTHTD NTJP2p (yeast) DSPKVRl-Lae DGMGN -LLMATVVDSFKYEPIAPGNDNLIKAPTVAA P163 (mouse) ATQKTQIÍjmADTNLGNIIJjnp.IAPNMPCrpiTGKNNV IVCVPNP? - RBPl (Mouse) FADECP - KPELLAIRFT, NABNAQKTKTKFBECRKE [SEQ ID NO. : twenty ] RBPl (Human) FADECP - KPELLAIRELNABNAQKFKTKFEECRKEI (SEQ ID NO.: 21] K0P2p (Yeast) DG I * XVTYIVEKQK EGRSFTKAIEDAKKEM (SEQ ID NO: 22] pl63 (Mouse) PLDEKQPTLPATMLIRVKTSEDADELHKILLEKKDAA [SEQ ID NO: 23] Table 6 pl63 (Mouse) (SEQ ID NO: 24] Met Ala Lys Arg Val Ala Glu Lys Glu Leu Thr Asp Arg Asn Trp Asp 1 5 10 15 Glu Glu Asp Glu Val Glu Glu Met Gly Thr Phe Ser Val Wing Ser Glu 20 25 30 Glu Val Met Lys Asn Arg Wing Val Lys Lys Wing Lys Arg Arg Asn Val 35 40 45 Gly Phe Glu Ser Asp Ser Gly Gly Wing Phe Lys Gly Phe Lys Gly Leu 50 55 60 Val Val Pro Ser Gly Gly Gly Gly Phe Ser Gly Phe Gly Gly Ser Gly 65 70 75 80 Gly Lys Pro Leu Glu Gly Leu Thr Asn Gly Asn Ser Thr Asp Asn Wing 85 90 95 Thr Pro Phe Ser Asn Val Lys Thr Wing Wing Glu Pro Lys Wing Wing Phe 100 105 110 Gly Ser Phe Wing Val Asn Gly Pro Thr Thr Leu Val Asp Lys Val Ser 115 120 125 Asn Pro Lys Thr Asn Gly Asp Ser Asn Gln Pro Pro Ser Ser Gly Pro 130 135 140 Wing Being Ser Thr Wing Cys Pro Gly Asn Wing Tyr His Lys Gln Leu Wing 145 150 155 160 Gly Leu Asn Cys Ser Val Arg Asp Trp He Val Lys His Val Asn Thr 165 170 175 Asn Pro Leu Cys Asp Leu Thr Pro He Phe Lys Asp Tyr Glu Arg Tyr 180 185 190 Leu Wing Thr He Glu Lys Gln Leu Glu Asn Gly Gly Gly Ser Ser 195 195 205 Glu Ser Gln Thr Asp Arg Wing Thr Wing Gly Met Glu Pro Pro Ser Leu 210 215 220 Phe Gly Ser Thr Lys Leu Gln Gln Glu Ser Pro Phe Ser Phe His Gly 225 230 235 240 Asn Lys Ala Glu Asp Thr Ser Glu Lys Val Glu Phe Thr Ala Glu Lys 245 250 255 Lys Ser Asp Wing Wing Gln Gly Wing Thr Ser Wing Being Phe Being Phe Gly 260 265 270 Lys Lys He Glu Being Wing Leu Gly Being Leu Being Ser Gly Being Leu 275 280 285 Thr Gly Phe Being Phe Being Wing Gly Being Ser Being Leu Phe Gly Lys Asp 290 295 300 Ala Ala Gln Ser Lys Ala Ala Ser Ser Leu Phe Ser Ala Lys Ala Ser 305 310 315 320 Glu Ser Pro Wing Gly Gly Gly Ser Glu Cys Arg Asp Gly Glu Glu 325 330 335 Glu Glu Asn Asp Glu Pro Pro Lys Val Val Val Tbr Glu Val Lys Glu 340 345 350 Glu Asp Ala Phe Tyr Ser Lys Lys Cys Lys Leu Phe Tyr Lys Lys Asp 355 360 365 Asn Glu Phe Lys Glu Lys Gly Val Gly Thr Leu His Leu Lys Pro Thr 370 375 380"Wing Thr Gln Lys Thr Gln Leu Leu Val Arg Wing Asp Thr Asn Leu Gly 385 390 395 400 Asn He Leu Leu Asn Val Leu He Wing Pro Asp Met Pro Cys Thr Arg 405 410 415 Thr Gly Lys Asn Asn Val Leu He Val Cys Val Pro Asn Pro Pro Leu 420 425 430 Asp Glu Lys Gln Pro Thr Leu Pro Wing Thr Met Leu lie Arg Val Lys 435 440 445 Thr Ser Glu Asp Wing Asp Glu Leu His Lys He Leu Leu Glu Lys Lys 450 455 460 Asp Wing 465 NÜP2 (Yeast) (SEQ ID NO: 25] Met Wing Lys Arg Val Wing Asp Wing Gln He Gln Arg Glu Thr Tyr Asp 1 5 10 15 Being Asn Glu Being Asp Asp Asp Val Thr Pro Being Thr Lys Val Wing Being 20 25 30 Being Wing Val Met Asn Arg Arg Lys He Wing Met Pro Lys Arg Arg Met 35 40 45 Wing Phe Lys Pro Phe Gly Ser Wing Lys Ser Asp Glu Thr Lys Gln Wing 50 55 60 Ser Ser Phe Ser Phe Leu Asn Arg Wing Asp Gly Thr Giy Glu Wing Gln 65 70 75 80 Val Asp Asn Ser Pro Thr Thr Glu Ser Asn Ser Arg Leu Lys Ala Leu 85 90 95 Asn Leu Gln Phe Lys Ala Lys Val Asp Asp Leu Val Leu Gly Lys Pro 100 105 110 Leu Wing Asp Leu Arg Pro Leu Phe Thr Arg Tyr Glu Leu Tyr He Lys 115 120 125 Asn He Leu Glu Pro Wing Val Lys Phe He Glu Asn Pro Thr Gln Thr 130 135 140 Lys Gly Asn Asp Ala Lys Pro Ala Lys Val Glu Asp Val Gln Lys Ser 145 150 155 160 Being Asp Being Being Glu Asp Glu Val Lys Val Glu Gly Pro Lys Phe 165 170 175 Thr He Asp Wing Lys Pro Pro He Ser Asp Ser Val Phe Ser Phe Gly 180 185 190 Pro Lys Lys Glu Asn Arg Lys Lys Asp Glu Ser Asp Ser Glu Asn Asp 195 200 205 lie Glu He Lys Gly Pro Glu Phe Lys Phe Ser Gly Thr Val Ser Ser 210 215 220 Asp Val Phe Lys Leu Asn Pro Ser Thr Asp Lys Asn Glu Lys Lys Thr 225 230 235 240 Glu Thr Asn Ala Lys Pro Phe Ser Phe Ser Ser Ala Thr Ser Thr Thr 245 250 255 Glu Gln Thr Lys Ser Lys Asn Pro Leu Ser Leu Thr Glu Wing Thr Lys 260 265 270 Thr Asn Val Asp Asn Asn Ser Lys Wing Glu Wing Ser Phe Thr Phe Gly 275 280 285 Thr Lys His Wing Wing Asp Ser Gln Asn Asp Lys Pro Be Phe Val Phe 290 295 300 Gly Gln Ala Ala Ala Lys Pro Ser Leu Glu Lys Ser Ser Phe Thr Phe 305 310 315 320 Gly Ser Thr Thr He Glu Lys Lys Asn Asp Glu Asn Ser Thr Ser Asn 325 330 335 Be Lys Pro Glu Lys Be Ser Asp Be Asn Asp Be Asp Pro Be Phe 340 345 350 Ser Phe Ser He Pro Ser Lys Asn Thr Pro Asp Wing Ser Lys Pro Ser 355 360 365 Phe Ashe Phe Gly Val Pro As As Ser Lys Asn Glu Thr Ser Lys Pro 370 375 380 Val Phe Ser Phe Gly Ala Ala Thr Pro Ser Ala Lys Glu Ala Ser Gln 385 390 395 400 Glu Asp Asp Asn_Asn Asn Val Glu Lys Pro Ser Ser Lys Pro Ala Phe 405 410 415 Asn Phe He Ser Asn Wing Gly Thr Glu Lys Glu Lys Glu Ser Lys Lys 420 425 430 Asp Ser Lys Pro Wing Phe Ser Phe Gly He Ser Asn Gly Ser Glu Ser 435 440 445 Lys Asp Ser Asp Lys Pro Ser Leu Pro Ser Wing Val Asp Gly Glu Asn 450 ~ 455 460 Asp Lys Lys Glu Wing Thr Lys Pro Wing Phe Phe Gly He Asn Thr Asn 465 470 475 480 Thr Thr Lys Thr Wing Asp Thr Lys Wing Pro Thr Phe Thr Phe Gly Ser 485 490 495 Be Ala Leu Ala Asp Asn Lys Glu Asp Val Lys Lys Pro Phe Ser Phe 500 505 510 Gly Thr Ser Gln Pro Asn Asn Thr Pro Be Phe Ser Phe Gly Lys Thr 515 520 525 Thr Wing Asn Leu Pro Wing Asn Being Ser Thr Ser Pro Wing Pro Ser He 530 535 540 Pro Ser Thr Gly Phe Lys Phe Ser Leu Pro Phe Glu Gln Lys Gly Ser 545 550 555 560 Gln Thr Thr Thr Asn Asp Ser Lys Glu Glu Ser Thr Thr Glu Wing Thr 565 570 575 Gly Asn Glu Ser Gln Asp Wing Thr Lys Val Asp Wing Thr Pro Glu Glu 580 585 590 Ser Lys Pro He Asn Leu Gln Asn Gly Glu Glu Asp Glu Val Wing Ala 595 600 605 Phe Ser Lys Wing Lys Leu Met Thr Phe Asn Wing Glu Thr Lys Ser Tyr 610 615 620 Asp Ser Arg Gly Val Gly Glu Met Lys Leu Leu Lys Lys Lys Asp Asp 625 630 635 640 Pro Ser Lys Val Arg Leu Leu Cys Arg Ser Asp Gly Met Gly Asn Val 645 650 655 Leu Leu Asn Wing Thr Val Val Asp Ser Phe Lys Tyr Glu Pro Leu Wing 660 665 670 Pro Gly Asn Asn Leu He Lys Wing Pro Thr Val Wing Wing Asp Gly 675 680 685 Lys Thr Tyr He Val Lys Phe Lys Gln Lys Glu Glu Gly Arg Ser Phe 690 695 700 Thr Lys Ala He Glu Asp Ala Lys Lys Glu Lys 705 710 715 - 18 -_ Table 7 Detection of associations between p27 and p163 in HeLa cells Precipitation of the total protein of HeLa cells transfected with Precipitation with C V-p27 CMV-p27 + CMV-Nap CMV-Nap2 Specific antibodies for - + + Nap2 Specific antibodies for + ++ -p27 Table 8: [SEQ ID NO .: 26] Met Ala Lys Arg Val Ala Glu Lys Glu Leu Thr Asp Arg Asn Trp Asp 1 5 10 15 Glu Glu Asp Glu Val Glu Glu Met Gly Thr Phe Ser Val Wing Ser Glu 20 25 30 Glu Val Met Lys Asn Arg Wing Val Lys Lys Wing Lys Arg Arg Asn Val 35 40 45 Gly Phe Glu Ser Asp Ser Gly Gly Wing Phe Lys Gly Phe Lys Gly Leu 50 55 60 Val Val Pro Ser Gly Gly Gly Gly Phe Ser Gly Phe Gly Gly Ser Gly 65 70 75 80 Gly Lys Pro Leu Glu Gly Leu Thr Asn Gly Asn Ser Thr Asp Asn Wing 85 90 95 Thr Pro Phe Ser Asn Val Lys Thr Wing Wing Glu Pro Lys Wing Wing Phe 100 105 110 Gly Ser Phe Wing Val Asn Gly Pro Phe Thr Wing Glu Lys Lys Ser Asp 115 120 125 Wing Wing Gln Gly Wing Thr Ser Wing Being Phe Ser Phe Gly Lys Lys He 130 135 140 Glu be Ser Ala Leu Gly Ser Leu Ser Ser Gly Ser Leu Thr Gly Phe 145 150 155 160 Being Phe Being Wing Gly Being Ser Being Leu Phe Gly Lys Asp Wing Wing Gln 165 170 175 Ser Lys Wing Wing Ser Ser Leu Phe Ser Wing Lys Wing Ser Glu Ser Pro 180 185 190 Wing Gly Gly Gly Ser Glu Cys Arg Asp Gly Glu Glu Glu Glu Asn 195 200 205 Asp Glu Pro Pro Lys Val Val Val Thr Val Val Glu Glu Glu Asp Ala 210 215 220 Phe Tyr Ser Lys Lys Cys Lys Leu Phe Tyr Lys Lys Asp Asn Glu Phe 225 230 235 240 Lys Glu Lys Gly Val Gly Thr Leu His Leu Lys Pro Thr Ala Thr Gln 245 250 255 Lys Thr Gln Leu Leu Val Arg Wing Asp Thr Asn Leu Gly Asn He Leu 260 265 270 Leu Asn Val Leu He Wing Pro Asn Met Pro Cys Thr Arg Thr Gly Lys 275 280 285 Asn Asn Val Leu He Val Cys Val Pro Asn Pro Pro Leu Asp Glu Lys 290 295 300 Gln Pro Thr Leu Pro Wing Thr Met Leu He Arg Val Lys Thr Ser Glu 305 310 315 320 Asp Ala Asp Glu Leu His Lys He Leu Leu Glu Lys Lys Asp Ala 325 330 335 Table 9: [SEQ ID NO .: 27] Met Ala Lys Arg Val Ala Glu Lys Glu Leu Thr Asp Arg Asn Trp Asp 1 5 10 15 Glu Glu Asp Glu Val Glu Glu Met Gly Thr Phe Ser Val Wing Ser Glu 20 25 30 Glu Val Met Lys Asn Arg Wing Val Lys Lys Wing Lys Arg Arg Asn Val 35 40 45 Gly Phe Glu Ser Asp Ser Gly Gly Wing Phe Lys Gly Phe Lys Gly Leu 50 55 60 Val Val Pro Ser Gly Gly Gly Gly Phe Ser Gly Phe Gly Gly Ser Gly 65 70 75 80 Gly Lys Pro Leu Glu Gly Leu Thr Asn Gly Asn Ser Thr Asp Asn Wing 85 90 95 Thr Pro Phe Ser Asn Val Lys Thr Wing Wing Glu Pro Lys Wing Wing Phe 100 105 110 Gly Ser Phe Wing Val Asn Gly Pro Thr Thr Leu Val Asp Lys Val Ser 115 120 125 Asn Pro Lys Thr Asn Gly Asp Ser Asn Gln Pro Pro Ser Ser Gly Pro 130 135 140 Wing Being Ser Thr Wing Cys Pro Gly Asn Wing Tyr His Lys Gln Leu Wing 145 150 155 160 Gly Leu Asn Cys Ser. Val Arg Asp Trp He Val Lys His Val Asn He 165 170 175 Asn Pro Leu Cy3 Asp Leu Thr Pro He Phe Lys Asp Tyr Glu Arg Tyr 180 185 190 Leu Wing Thr He Glu Lys Gln Leu Glu Asn Gly Gly Gly Being Ser 195 200 205 Glu Ser Gln Thr Asp Arg Wing Thr Wing Gly Met Glu Pro Pro Ser Leu 210 215 220 Phe Gly Ser Thr Lys Leu Gln Gln Glu Ser Pro Phe be Phe His Gly 225 230 235 240 - - Asn Lys Ala Glu Asp Thr Ser Glu Lys Val Glu Phe Thr Ala Glu Lys 245 250 255 Lys Ser Asp Wing Wing Gln Gly Wing Thr Ser Wing Being Phe Being Phe Gly 260 265 270 Lys Lys He Glu Being Wing Leu Gly Being Leu Being Ser Gly Being Leu 275 280 285 Thr Gly Phe Being Phe Being Wing Gly Being Ser Being Leu Phe Gly Lys Asp 290 295 300 Ala Ala Glu Lys Glu Leu 305 310 Table 10: [SEQ ID NO .: 28] Thr Thr Leu Val Asp Lys Val Ser Asn Pro Lys Thr Asn Gly Asp Ser 1 5 10 15 Asn Gln Pro Pro Ser Ser Gly Pro Wing Ser Thr Wing Cys Pro Gly 20 25 30 Asn Wing Tyr His Lys Gln Leu Wing Gly Leu Aen Cys Ser Val Arg Asp 35 40 45 Trp He Val Lys His Val Asn Thr Asn Pro Leu Cys Asp Leu Thr Pro 50 55 60 He Phe Lys Asp Tyr Glu Arg Tyr Leu Wing Thr He Glu Lys Gln Leu 65 70 75 80 Glu Asn Gly Gly Gly Being Ser Glu Being Gln Thr Asp Arg Ala Thr 85 90 95 Wing Gly Met Glu Pro Pro Ser Leu Phe Gly Ser Thr Lys Leu Gln Gln 100 105 110 Glu Ser Pro Phe Ser Phe His Gly Asn Lys Wing Glu Asp Thr Ser Glu 115 120 125 Lys Val Glu Phe 130 Table 11: GUC sequences in pl63 Nucleotide positions Sequence The interacting domain comprises amino acids 121-252 of the mouse sequence, to which the numbering refers. This corresponds to nucleotides 685-1078 of the mouse sequence.

Table 12a: pairs of selected primers "Note" Length GC% Site Name 5"* 3 * 5.8 108 43.5 122. .143 Above: AGAAAGCAAAGCGCAGAAATGT [SEQ ID NO .: 29] 229. .209 Below: CAAATCCAGAAAAGCGTCCTC [SEQ ID NO .: 30] 6. 7 119 42.0 104. .127 Above: TGAAGAATAGAGCCATAAAGAAAG [SEQ ID NO .: 31] 240. .220 Below: AGAAAAGCGTCCTCCTCCAGA [SEQ ID NO. : 32] 23. 3 137 43.8 104. .127 Above: TGAAGAATAGAGCCATAAAGAAAG [SEQ ID NO .: 33] 204. .220 Below: AGCGCCACTAACCAAATCCAGA [SEQ ID NO .: 34] . 7 100 44.0 122. .143 Above: AGAAAGCAAAGCGCAGAAATGT [SEQ ID NO .: 35] 221.. 200 Below: GAAAAGCGTCCTCCTCCAGAAG [SEQ? D NO .: 36] 48. 7 122 46.7 123. .144 Above: GAAAGCAAAGCGCAGAAATGTT [SEQ ID NO .: 37] 244.. 224 Below: CTCCAGCGCCACTACCAAATC [SEQ ID NO .: 38] Table 12b: A pair of selected primers '' Note '' Length GC% Site Name 5 * 3 * 51. 3 193 52.8 34. .53 Top CCCGCACGGAGCAGTTCAAG [SEQ ID NO .: 39] 226. .205 Below: GCAGCGGCAGATCCCAAGGTAG [SEQ ID NO .: 40] Table 12c.

A pair of selected primers Note Long. GC% Site Name 5"3 * 2.4 136 45.6 4. .20 Above: GGCATCCTTTTTCTCCA [SEQ ID NO .: 41] 139. .120 Aba ^ o: CGTTCTTATCGTCTCTGTGTTC [SEQ ID NO .: 42] 2. 5 120 45. .0 5. .23 Above: GCATCCTTTTTCTCCAGTA [SEQ ID NO. : 43] 139. .119 Bottom: TGTTCCAAATCCACCAAT [SEQ ID NO .: 44] 2. 7 100 48. .0 40. .58 Above: GTCTGCATCCTCGCTGGTT [SEQ ID NO .: 45] 139. .119 Bottom: CGTTCTTATCGTCTGTGTTCC [SEQ ID NO .: 46] 50. 0 105 44. .8 57. .75 Above: TTTTACCCGAATCAACAT [SEQ ID NO .: 47] 161. .141 Below: GTACGCGAACAGGGAAGAATA [SEQ ID NO .: 48] Table 13: Summary of growth experiments Ciclina D1 Nup2 Table 14: Sequences of the mutated p27 proteins compared to the 11 S D L H H C R D M E E A S Q R 1 G R Y E W Q E V E Majority 1 50 60 70 80! • 26 L T R D L E K H C R D M E E A S Q R K W N F D F Q H H C P L 2 G R Y E W Q E V E Clone 106 Protein 37 L T R D L E K H C R D M E E A S Q 0 K W N P D F Q N H L? G R Y E W Q E V E Clone 152 Protein 37 L T R D L E K H C R D M E E A S Q R K W N F D F Q N H K P L? G R Y E W Q E V E Clone 294 Protein 36 L T R D L B K H C R D M E E S O R K W K F D F O H H K P L Z G R Y E W Q E V S Clone 660 Protein 38 IR 1. T R D E K H C R D MI A L E S 0 R K W it r D r * 't * - K F? G R Y E K O E V | Clone 687 Protein 26 L T R D L E K H M E E A S Q R K W H F D P Q H H K P - >; ? G R Y E W Q E V E Clone 826 Protein 26 L T R D L E K H C R D M E E A S Q R K W N F D F Q H H r P L? G R Y E W Q E V E Clone 850 Prot? Ína 41 L T R D L E K H C R D M E S S Q R K W N F D F N H K P L E G R Y E H Q E V E Mouse p27 AS R G S L P E F Y Y R, P P P K S A C K, V L A Q E S Q D V S, S S R Q A V P L I G r Majority 90 100 11C 120 1 _ 1 1 1_ 66 R G S L P E F Y Y R P P JP P K S? C K Y? Q E S Q D V S G S R Q? V P I I G Clone 106 Protein 77 R G S L P E F Y Y R P P R P P K? A C K V L A Q E S Q D V S G S R Q A V P -. I G Clone 152 Protein 77 R G S L P E F Y Y P P P K S A C K V L A Q B S Q D V S G S R O A V P t 1 S Clone 660 Protein 78 | B R G S -. P E F | Y | rlR P P R t? P K S A C K V P A Q E S Q D V S G S R O A V P I- I | Clone 687 Protaína £ 6 R G S L P E F Y Y R P P R P P K S A C K V L A Q E S Q D V S G S R Q A V P L I G Clone 826 Protein 66 R G S L P E F Y Y (JP P R P P K S A C K V L A Q E S Q D V S G S R Q A V P L I G Clone 850 Protein 81 R G S L P E F Y Y R P P R P P K S A C K V L A Q E S Q D V S G S R Q A V P L I G Mouse p27 AS S Q A N S E D R H L V D Q M P D S S D K Q A G L A E Q C P O H R A S E D S Majority 130 140 ISO 1S0 105 S Q A N S E D R H L V D Q M P D S S D H Q A G L A E Q C P G R K A P S E S S Clone 106 Prot? N 117 S Q A N S E D R H L V D Q M P D S S D N Q A G L A E Q C G G R R R A A E D S Clone 152 Protein 117 S Q A N S E D R H L V D Q M P D S S D N G L A E Q C G H R K R P A A S D S Clone 294 Protein 116 S rj A N S E D R H I. V D Q H. P D S S D A Q A G E A C Q G G R K R P A A E D S Clone 660 Protein 118 [S D 0 A G L S S O C P 3 M R * C R f K E D [Clone 687 Protßma D N Q A G L A E Q C G M R K R A A E D S Clone 826 Protaina • O ¡Q A G L A E Q C p (- - - - - - - - - - - 1 clone 850 Protein 121 S Q A N S E D R H L V D Q M P S S D N Q A G L A E Q C G M R K R P A A E D S Mouse p27 AS - Majority Clone 106 Clone 152 Protein Clone 294 Proton Clone 660 Clone - R Clone 687 Clone R - Clone 826 Protein G - Clone 850 Protine Mouse p27 AS V D L Q P FRAN - FL - FM I P Majority Sequence SEQ ID NO: Majority 49 Clone 106 50 Clone 152 51 Clone 294 52 Clone 660 53 Clone 687 54 Clone 826 55 Clone 850 56 p27 (Mouse) 57 SEQUENCE PROTOCOL (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: Hoechst Marion Roussel Deutsc land GmbH (B) STREET: - (C) CITY: Frankfurt (D) FEDERAL STATE: - (E) COUNTRY: Germany (F) POSTAL CODE: 65926 (G) TELEPHONE: 069-305-305 (H) TELEFAX: 069-35-7175 (I) TELEX: - (ii) TITLE OF THE APPLICATION: Participating in a union for inhibitors of cyclin-dependent kinases and its use for the search of inhibitors, for the diagnosis or for the therapy of a disease (iii) NUMBER OF SEQUENCES: 57 (iv) READING FORM BY COMPUTER: (A) DATA SUPPORT: floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) LOGICAL SYSTEM: Patentln Relay n ° 1.0, version n "1.25 (EPA) (2) INFORMATION ABOUT SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1. . 17 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 1: CGGACAACTG TTGACCG 17 - - (2) INFORMATION ABOUT SEQ ID NO: 2: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple ( D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..20 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 2: TACTGTATGT ACATACAGTA 20 (2) INFORMATION ABOUT? EQ ID NO: 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..22 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3: GAATTGTGAG CGCTCACAAT TC 22 (2) INFORMATION ABOUT SEQ ID NO: 4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 42 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: ALN (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1.42 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 4: TCGAGTTTAC CACTCCCTAT CAGTGATAGA GAAAAGTGAA AG 42 (2) INFORMATION ABOUT SEQ ID NO: 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 12 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..12 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 5: TAATGATGGG CG 12 (2) INFORMATION ABOUT SEQ ID NO: 6: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 26 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..26 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 6: GGAAGCAGAC CACGTGGTCT GCTTCC 26 (2) INFORMATION ABOUT SEQ ID NO: 7: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 17 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..17 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 7: AGCAGGTGTT GGGAGGC 17 (2) INFORMATION ABOUT SEQ ID NO: 8: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 41 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..41 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 8: GGCCGATGGG CAGATAGAGG GGGCCGATGG GCAGATAGAG G 41 (2) INFORMATION ABOUT SEQ ID NO: 9: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 1958 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..1958 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 9: TCGAATTGGG TACCGGGCCC CCCCTCGAGG TCGACGGTAT CGATAAGCTT GATATCGAAT 60 TCGCGGCCGC TCGAGTTACA AGATGGCGGC CCCGGGCGCT CTCTTCACCG TTCTGTAGCA 120 GCTTCGGGCT GAGCGGATGT CTCTTCTTGT CCTCAGTGTC GGACTCAGAG ACACACGGCT 180 CCCGAGTTCT GCTGATCACG AAGTTCCCGG AGGCGCTCGA CGCACCGGAA TCTCCCAGCG 240 GCCGCGACCG CCGCCTCGGC CCTGCTCGCC GCGGCGCCGG GACTCCAGCG TGATCGGCGG 300 CGGCAGTCAA GGTTCACAAA AATGGCGAAG AGAGTTGCGG AGAAGGAGTT GACTGACAGG 360 AACTGGGATG AGGAAGACGA AGTTGAAGAG ATGGGAACAT TCTCAGTGGC CAGTGAGGAA 420 GTCATGAAGA ACAGAGCCGT AAAGAAGGCA AAGCGCAGAA ACGTTGGATT TGAATCTGAT 480 AGCGGAGGAG CCTTTAAAGG TTTCAAAGGT TTGGTTGTGC CTTCTGGAGG AGGAGGGTTT 540 TCTGGATTTG GTGGCTCTGG AGGAAAGCCT CTGGAAGGAC TGACAAATGG AAACAGCACA 600 GACAATGCCA CGCCCTTCTC CAATGTAAAG ACAGCAGCAG AGCCCAAGGC AGCCTTTGGT 660 TCTTTTGCTG TGAATGGCCC TACTACCTTG GTGGATAAAG TTTCAAATCC AAAAACTAAT 720 - - GGGGACAGCA ATCAGCCGCC CTCCTCCGGC CCTGCTTCCA GTACCGCCTG CCCTGGGAAT 780 GCCTATCACA AGCAGCTGGC TGGCTTGAAC TGCTCCGTCC GCGATTGGAT AGTGAAGCAC 840 GTGAACACAA ACCCGCTTTG TGACCTGACT CCCATTTTTA AAGACTATGA GAGATACTTG 900 GCGACGATCG AGAAGCAGCT TGAGAATGGA GGCGGCAGCA GTTCTGAGAG CCAGACAGAC 960 AGGGCGACGG CTGCAATGGA GCCTCCTTCC CTTTTTGGTT CAACAAAACT ACAGCAAGAG 1020 TCACCATTTT CATTTCATGG CAACAAAGCG GAGGACACAT CTGAAAAGGT GGAGTTTACA 1080 GCAGAAAAGA AATCGGACGC AGCACAAGGA GCAACAAGTG CCTCGTTTAG TTTCGGCAAG 1140 AAAATTGAGA GCTCGGCTTT GGGCTCGTTA AGCTCTGGCT CCCTAACTGG GTTTTCATTC 1200 TCTGCTGGAA GCTCCAGCTT GTTTGGTAAA GATGCTGCCC AGAGTAAAGC AGCCTCTTCG 1260 CTGTTCTCTG CTAAAGCATC CGAGAGTCCG GCAGGAGGCG GCAGCAGCGA GTGCAGAGAT 1320 GGTGAAGAAG AGGAGAATGA CGAGCCACCC AAGGTAGTGG TGACCGAAGT AAAGGAAGAG 1380 GATGCTTTCT ACTCCAAAAA ATGTAAACTA TTTTACAAGA AAGACAACGA ATTTAAAGAG 1440 AAGGGTGTGG GGACCCTGCA TTTAAAACCC ACAGCAACTC AGAAGACCCA GCTCTTGGTG 1500 CGGGCAGACA CCAACCTAGG CAACATACTG CTGAATGTTC TGATCGCCCC CAACATGCCG 1560 TGCACCCGGA CAGGAAAGAA CAACGTCCTT ATCGTCTGTG TCCCCAACCC CCCACTCGAT 1620 GAGAAGCAGC CCACTCTCCC GGCCACCATG CTGATCCGGG TGAAGACGAG CGAGGATGCC 1680 GATGAATTGC ACAAGATTTT ACTGGAGAAA AAGGATGCCT GAGCACTGAG GCTGACCAAG 1740 GCATGTTGCC ACGTTGCTGC TTCCCCTCCG TCCCTAACTT AGTCACATTC TTTCCTCTTC 1800 TACTGTGACA TTCTGAGAAC TTCTAGGTAA CTTGAACTTT TGTGAGGAAG ATTAAGGCCA 1860 ATAAATCCTT TCAGTGGCGG CCGCGAATTC CTGCAGCCCG GGGGATCCAC TAGTTCTAGA 1920 GCGGCCGCCA CCGCGGTGGA GCTCCAGCTT TTGGGAGA 1958 (2) INFORMATION ABOUT SEQ ID NO: 10: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 24 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..24 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 10: Met Ala Lys Arg Val Ala Glu Lys Glu Leu Thr Asp Arg Asn Trp Asp 1 5 10 15 Glu Glu Asp Glu Val Glu Glu Met 20 (2) INFORMATION ABOUT SEQ ID NO: 11: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 24 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..24 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 11: Met Wing Lys Arg Val Wing Asp Wing Gln lie Gln Arg Glu Thr Tyr Asp 1 5 10 15 Ser Asn Glu Ser Asp Asp Asp Val 20 (2) INFORMATION ABOUT SEQ ID NO: 12: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 60 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) FEATURES: (A) NAME / KEY: protein (B) SITUATION: 1..60 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12: Asn Gln Pro Pro Ser Ser Gly Pro Ala Ser Ser Thr Ala Cys Pro Gly 1 5 10 15 Asn Wing Tyr His Lys Gln Leu Wing Gly Leu Asn Cys Ser Val Arg Asp 20 25 30 Trp lie Val Lys His Val Asn Thr Asn Pro Leu Cys Asp Leu Thr Pro 35 40 45 lie Phe Lys Asp Tyr Glu Arg Tyr Leu Ala Thr lie 50 55 60 (2) INFORMATION ABOUT SEQ ID NO: 13: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 60 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..60 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 13: Asn Arg Wing Asp Gly Thr Gly Glu Wing Gln Val Asp Asn Ser Pro Thr 1 5 10 15 Thr Glu Ser Asn Ser Arg Leu Lys Ala Leu Asn Leu Gln Phe Lys Wing 20 25 30 Lys Val Asp Asp Leu Val Leu Gly Lys Pro Leu Wing Asp Leu Arg Pro 35 40 45 Leu Phe Thr Arg Tyr Glu Leu Tyr He Lys Asn He 50 55 60 (2) INFORMATION ABOUT SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..51 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 14: Wing Thr Wing Gly Met Glu Pro Pro Ser Leu Phe Gly Ser Thr Lys Leu 1 5 10 15 Gln Gln Glu Ser Pro Phe Ser Phe His Gly Asn Lys Wing Glu Asp Thr 20 25 30 Ser Glu Lys Val Glu Phe Thr Ala Glu Lys Lys Ser Asp Ala Ala Gln 35 40 45 Gly Ala Thr 50 (2) INFORMATION ABOUT SEQ ID NO: 15: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..51 - - (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 15: Wing Asn Being Ser Thr Ser Pro Wing Pro Being Pro Pro Thr Gly Phe 1 5 10 15 Lys Phe Ser Leu Pro Phe Glu Gln Lys Gly Ser Gln Thr Thr Thr Asn 20 25 30 Asp Ser Lys Glu Glu Ser Thr Thr Glu Wing Thr Gly Asn Glu Ser Gln 35 40 45 Asp Ala Thr 50 (2) INFORMATION ABOUT SEQ ID NO: 16: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 34 amino acids (3) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..34 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 16: His Gly Asn Lys Ala Glu Asp Thr Ser Glu Lys Val Glu Phe Thr Ala 1 5 10 15 Glu Lys Lys Ser Asp Wing Wing Gln Gly Wing Thr Ser Wing Being Phe Ser 20 25 30 Phe Gly (2) INFORMATION ABOUT SEQ ID NO: 17: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 34 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple \ u?? VrviJ - u?. i iuci (ii) TYPE OF THE MOLECULE: protein -. • (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..34 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 17: Asn Gly Ser Glu Ser Lys Asp Ser Asp Lys Pro Ser Leu Pro Ser Wing 1 5 10 15 Val Asp Gly Glu Asn Asp Lys Lys Glu Wing Thr Lys Pro Wing Phe Ser 20 25 30 Phe Gly (2) INFORMATION ABOUT SEQ ID NO: 18: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 40 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..40 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 18: Leu Gly Asn He Leu Leu Asn Val Leu He Wing Pro Asn Met Pro Cys 1 5 10 15 Thr Arg Thr Gly Lys Asn Asn Val Leu He Val Cys Val Pro Asn Pro 20 25 30 Pro Leu Asp Glu Lys Gln Pro Thr 35 40 (2) INFORMATION ABOUT SEQ ID NO: 19: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 40 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..40 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 19: Met Gly Asn Val Leu Leu Asn Wing Thr Val Val Asp Ser Phe Lys Tyr 1 5 10 15 Glu Pro Leu Wing Pro Gly Asn Asn Asn Leu He Lys Wing Pro Thr Val 20 25 30 Wing Wing Asp Gly Lys Leu Val Thr 35 40 (2) INFORMATION ABOUT SEQ ID NO: 20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 157 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: "(A) NAME / KEY: protein (B) SITUATION: 1..157 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 20: Asp Ser His Wing Asp His Asp Thr Ser Thr Glu Asn Wing Asp Glu Ser 1 5 10 15 Thr Thr His Pro Gln Phe Glu Pro He Val Ser Val Pro Glu Gln Glu 20 25 30 - - He Lys Thr Leu Glu Glu Asp Glu Glu Glu Leu Phe Lys Met Arg Ala 35 40 45 Lys Leu Phe Arg Phe Wing Ser Glu Asn Asp Leu Pro Glu Trp Lys Glu 50 55 60 Pro Arg Hiß Gly Asp Val Lys Leu Leu Lys His Lys Glu Lys Gly Thr 65 70 75 80 He Arg Leu Leu Met Arg Arg Asp Lys Thr Leu Lys He Cys Wing Asn 85 90 95 His Tyr He Thr Pro Met Met Glu Leu Lys Pro Asn Wing Gly Ser Asp 100 105 110 Arg Wing Trp Val Trp Asn Thr His Thr Asp Phe Wing Asp Glu Cys Pro 115 120 125 Lys Pro Glu Leu Leu Wing He Arg Phe Leu Asn Wing Glu Asn Wing Gln 130 135 140 Lys Phe Lys Thr Lys Phe Glu Glu Cys Arg Lys Glu He 145 150 155 (2) INFORMATION ABOUT SEQ ID NO: 21: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 157 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..157 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 21: Asp Ser His Wing Asp His Asp Thr Ser Thr Glu Asn Wing Asp Glu Ser 1 5 10 15 Asn His Aap Pro Gln Phe Glu Pro He Val Ser Val Pro Glu Gln Glu 20 25 30 He Lys Thr Leu Glu Glu Asp Glu Glu Glu Leu Phe Lys Met Arg Ala 35 40 45 Lys Leu Phe Arg Phe Wing Ser Glu Asn Asp Leu Pro Glu Trp Lys Glu 50 55 60 Arg Gly Thr Gly Asp Val Lys Leu Leu Lys His Lys Glu Lys Gly Thr 65 70 75 80 He Arg Leu Leu Met Arg Arg Asp Lys Thr Leu Lys He Cys Wing Asn 85 90 95 His Tyr He Thr Pro Met Met Glu Leu Lys Pro Asn Wing Gly Ser Asp 100 105 110 Arg Wing Trp Val Trp Asn Thr His Thr Asp Phe Wing Asp Glu Cyß Pro 115 120 125 Lys Pro Glu Leu Leu Wing He Arg Phe Leu Asn Wing Glu Asn Wing ßln 130 135 140 Lys Phe Lys Thr Lys Phe Glu Glu Cys Arg Lys Glu He 145 150 155 (2) INFORMATION ABOUT SEQ ID NO: 22: (i) SEQUENCE CHARACTERISTICS: ÍA) LENGTH: 158 amino acids, B) TYPE: amino acid (C) CHAIN FORM: simple! D) TOPOLOGY: linear (li) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..158 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 22: Ser Gln Thr Thr Thr Asn Asp Ser Lys Glu Glu Ser Thr Thr Glu Wing 1 5 10 15 Thr Gly Asn Glu Ser Gln Asp Wing Thr Lys Val Asp Wing Thr Pro Glu 20 25 30 Glu Ser Lys Pro He Asn Leu Gln Asn Gly Glu Glu Asp Glu Val Wing 35 40 45 Leu Phe Ser Gln Lys Wing Lys Leu Met Thr Phe Asn Wing Glu Thr Lys 50 55 60 Ser Tyr Asp Ser Arg Gly Val Gly Glu Met Lys Leu Leu Lys Lys Lys 65 70 75 80 Asp Asp Ser Pro Lys Val Arg Leu Leu Cys Arg Ser Asp Gly Mßt Gly 85 90 95 Asn Val Leu Asu Ala Thr Val Val Asp Ser Phe Lys Tyr Glu Pro 100 105 110 Leu Ala Pro Gly Asn Asp Asn Leu He Lys Ala Pro Thr Val Ala Ala 115 120 125 -_- - - - (2) INFORMATION ABOUT SEQ ID NO: 23: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 160 amino acids (B) TYPE: amino acid (C) FORM CHAIN: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..160 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 23: Gln Ser Lys Ala Ala Ser Ser Leu Phe Ser Ala Lys Ala Ser Glu Ser 1 5 10 15 Pro Wing Gly Gly Gly Ser Glu Cys Arg Asp Gly Glu Glu Glu Glu 20 25 30 Asn Asp Glu Pro Pro Lys Val Val Val Thr Glu Val Lys Glu Aslu 35 40 45 Wing Phe Tyr Ser Lys Lys Cys Lys Leu Phe Tyr Lys Lys Asp Asn Glu 50 55 60 Phe Lys Glu Lys Gly Val Gly Thr Leu His Leu Lys Pro Thr Ala Thr 65 70 75 80 Gln Lys Thr Gln Leu Leu Val Arg Wing Asp Thr Asn Leu Gly Asn He 85 90 95 Leu Leu Asn Val Leu He Wing Pro Asn Met Pro Cys Thr Arg Thr Gly 100 105 110 Lys Asn Asn Val Leu He Val Cys Val Pro Asn Pro Leu Asp Glu Lys 115 120 125 Gln Pro Thr Leu Pro Wing Thr Met Leu He Arg Val Lys Thr Ser Glu 130 135 140 Asp Wing Asp Glu Leu His Lys He Leu Leu Glu Lys Lys Asp Ala Wing 145 150 155 160 (2) INFORMATION ABOUT SEQ ID NO: 24: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 466 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein [ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1.4666 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 24: Met Ala Lys Arg Val Ala Glu Lys Glu Leu Thr Asp Arg Asn Trp Asp 1 5 10 15 Glu Glu Asp Glu Val Glu Glu Met Gly Thr Phe Ser Val Wing Ser Glu 20 25 30 Glu Val Met Lys Asn Arg Wing Val Lys Lys Wing Lys Arg Arg Asn Val 35 40 45 Gly Phe Glu Ser Asp Ser Gly Gly Wing Phe Lys Gly Phe Lys Gly Leu 50 55 60 Val Val Pro Ser Gly Gly Gly Gly Phe Ser Gly Phe Gly Gly Ser Gly 65 70 75 80 Gly Lys Pro Leu Glu Gly Leu Thr Asn Gly Asn Ser Thr Asp Asn Wing 85 90 95 Thr Pro Phe Ser Asn Val Lys Thr Wing Wing Glu Pro Lys Wing Wing Phe 100 105 110 Gly Ser Phe Wing Val Asn Gly Pro Thr Thr Leu Val Asp Lys Val Ser 115 120 125 Asn Pro Lys Thr Asn Gly Asp Ser Asn Gln Pro Pro Ser Ser Gly Pro 130 135 140 Wing being Thr Ala Cys Pro Gly Asn Wing Tyr His Lys Gln Leu Wing 145 150 155 160 Gly Leu Asn Cys Ser Val Arg Asp Trp He Val Lys His Val Asn Thr 165 170 175 Asn Pro Leu Cys Asp Leu Thr Pro He Phe Lys Asp Tyr Glu Arg Tyr 180 185 190 Leu Wing Thr He Glu Lys Gln Leu Glu Asn Gly Gly Gly Ser Ser 195 195 205 Glu Ser Gln Thr Asp Arg Wing Thr Wing Gly Met Glu Pro Pro Ser Leu 210 215 220 Phe Gly Ser Thr Lys Leu Gln Gln Glu Ser Pro Phe Ser Phe His Gly 225 230 235 240 Asn Lys Ala Glu Asp Thr Ser Glu Lys Val Glu Phe Thr Ala Glu Lys 245 250 255 Lys Ser Asp Ala Wing Gln Gly Wing Thr Being Wing Being Phe Being Phe Gly 260 265 270 Lys Lys He Glu Being Wing Leu Gly Being Leu Being Ser Gly Being Leu 275 280 285 Thr Gly Phe Being Phe Being Wing Gly Being Being Leu Phe Gly Lys Asp 290 295 300 Ala Ala Gln Ser Lys Ala Ala Ser Ser Leu Phe Ser Ala Lys Ala Ser 305 310 315 320 Glu Ser Pro Gly Wing Gly Gly Ser Glu Cys Arg Asp Gly Glu Glu 325 330 335 Glu Glu Asn Asp Glu Pro Pro Lys Val Val Val Thr Glu Val Lys Glu 340 345 350 Glu Asp Ala Phe Tyr Ser Lys Lys Cys Lys Leu Phe Tyr Lys Lys Asp 355 360 365 Asn Glu Phe Lys Glu Lys Gly Val Gly Thr Leu His Leu Lys Pro Thr 370 375 380 Wing Thr Gln Lys Thr Gln Leu Leu Val Arg Wing Asp Thr Asn Leu Gly 385 390 395 400 Asn He Leu Leu Asn Val Leu He Wing Pro Asn Met Pro Cys Thr Arg 405 410 415 Thr Gly Lys Asn Asn Val Leu He Val Cys Val Pro Asn Pro Pro Leu 420 425 430 Asp Glu Lys Gln Pro Thr Leu Pro Wing Thr Met Leu He Arg Val Lys 435 440 445 Thr Ser Glu Asp Wing Asp Glu Leu His Lys He Leu Leu Glu Lys Lys 450 455 460 Asp Wing 465 (2) INFORMATION ABOUT SEQ ID NO: 25: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 715 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE D? THE MOLECULE: proceína (ix) CHARACTERISTICS: (A) NAME / KEY: prsteína (B) SITUATION: 1..715 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 25: Met Wing Lys Arg Val Wing Asp Wing Gln He Gln Arg Glu Thr Tyr Asp 1 5 10 15 Ser Asn Glu be Asp Asp Asp Val Thr Pro Ser Thr Lys Val Wing Ser 20 25 30 Ser Wing Val Met Asn Arg Arg Lys He Wing Met Pro Lys Arg Arg Met 35 40 45 Wing Phe Lys Pro Phe Gly Ser Wing Lys Ser Asp Glu Thr Lys Gln Wing 50 55 60 Ser Ser Phe Ser Phe Leu Asn Arg Wing Asp Gly Thr Gly Glu Wing Gln 65 70 75 80 Val Asp Asn Ser Pro Thr Thr Glu Ser Asn Ser Arg Leu Lys Ala Leu 85 90 95 Asn Leu Gln Phe Lys Wing Lys Val Asp Asp Leu Val Leu Gly Lys Pro 100 105 110 Leu Wing Asp Leu Arg Pro Leu Phe Thr Arg Tyr Glu Leu Tyr He Lys 115 120 125 Asn He Leu Glu Wing Pro Val Lys Phe He Glu Asn Pro Thr Gln Thr 130 135 140 Lys Gly Asn Asp Ala Lys Pro Ala Lys Val Glu Asp Val Gln Lys Ser 145 150 155 160 Being Asp Being Being Glu Asp Glu Val Lys Val Glu Gly Pro Lys Phe 165 170 175 Thr He Asp Wing Lys Pro Pro He Ser Asp Ser Val Phe Ser Phe Gly 180 185 190 Pro Lys Lys Glu Asn Arg Lys Lys Asp Glu Ser Asp Ser Glu Assa Asp 195 200 205 He Glu He Lys Gly Pro Glu Phe Lys Phe Ser Gly Thr Val Ser Ser 210 215 220 Asp Val Phe Lys Leu Asn Pro Ser Thr Asp Lys Asn Glu Lys Lys Thr 225 230 235 240 Glu Thr Asn Ala Lys Pro Phe Ser Phe Ser Ser Ala Thr Ser Thr Thr 245 250 255 Glu Gln Thr Lys Ser Lys Asn Pro Leu Ser Leu Thr Glu Wing Thr Lys 260 265 270 Thr Asn Val Asp Asn Asn Ser Lys Wing Glu Wing Ser Phe Thr Phe Gly 275 280 285 Thr Lys His Wing Wing Asp Ser Gln Asn Asn Lys Pro Be Phe Val Phe 290 295 300 Gly Gln Ala Ala Ala Lys Pro Ser Leu Glu Lys Ser Ser Phe Thr Phe 305 310 315 320 Gly Ser Thr Thr He Glu Lys Lys Asn Asp Glu Asn Ser Thr Ser Asn 325 330 335 Ser Lys Pro Glu Lys Ser Ser Asp Ser Asn Asp Ser Asn Pro S &x: Phe 340 345 350 Ser Phe Ser He Pro Ser Lys Asn Thr Pro Asp Wing Ser Lys Pro Ser 355 360 365 Phe Ashe Phe Gly Val Pro Asn Ser Ser Lys Asn Glu Thr Ser Lys Pro 370 375 380 Val Phe Ser Phe Gly Wing Wing Thr Pro Ser Wing Lys Glu Wing Ser Gln 385 390 395 400 Glu Asp Asp Asn Asn Asn Val Glu Lys Pro Ser Ser Lys Pro Ala Phe 405 410 415 Asn Phe He Ser Asn Wing Gly Thr Glu Lys Glu Lys Glu Ser Lys Lyß 420 425 430 Asp Ser Lys Pro Wing Phe Ser Phe Gly He Ser Asn Gly Ser Glu Ser 435 440 445 Lys Aßp Ser Asp Lys Pro Ser Leu Pro Ser Wing Val Asp Gly Glu Asn 450 455 460 Asp Lys Lys Glu Wing Thr Lys Pro Wing Phe Phe Gly He Asn Thr Asn 465 470 475 480 Thr Thr Lys Thr Wing Asp Thr Lys Wing Pro Thr Phe Thr Phe Gly Ser 485 490 495 Be Wing Leu Wing Asp Asn Lys Glu Asp Val Lys Lys Pro Phe Ser Phe 500 505 510 Gly Thr Ser Gln Pro Asn Asn Thr Pro Ser Phe Ser Phe Gly Lys T r 515 520 525 Thr Wing Asn Leu Pro Wing Asn be Ser Thr Ser Pro Ala Pro Ser He 530 535 540 Pro Ser Thr Gly Phe Lys Phe Ser Leu Pro Phe Glu Gln Lys Gly Ser 545 550 555 560 Gln Thr Thr Thr Asn Asp Ser Lys Glu Glu Ser Thr Thr Glu Wing Thr 565 570 575 Gly Asn Glu Ser Gln Asp Wing Thr Lys Val Asp Wing Thr Pro Glu Glu 580 585 590 Ser Lys Pro He Asn Leu Gln Asn Gly Glu Glu Asp Glu Val Wing Ala 595 600 605 Phe Ser Lys Wing Lys Leu Met Thr Phe Asn Wing Glu Thr Lys Ser Tyr 610 615 620 Asp Ser Arg Gly Val Gly Glu Met Lys Leu Leu Lys Lys Lys Asp Asp 625 630 635 640 Pro Ser Lys Val Arg Leu Leu Cys Arg Ser Asp Gly Met Gly Asn Val 645 650 655 Leu Leu Aßn Wing Thr Val Val Asp Ser Phe Lys Tyr Glu Pro Leu Wing 660 665 670 Pro Gly Asn Asp Asn Leu He Lys Wing Pro Thr Val Wing Wing Asp Gly 675 680 685 Lys Thr Tyr He Val Lys Phe Lys Gln Lys Glu Glu Gly Arg Ser Phe 690 695 700 Thr Lys Ala He Glu Asp Ala Lys Lys Glu Lys 705 710 715 (2) INFORMATION ABOUT SEQ ID NO: 26: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 335 amino acids (B) ) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..335 (i) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 26: Met Ala Lys Arg Val Ala Glu Lys Glu Leu Thr Asp Arg Asp Trp Asp 1 5 10 15 Glu Glu Asp Glu Val Glu Glu Met Gly Thr Phe Ser Val Wing Ser Glu 20 25 30 Glu Val Met Lys Asn Arg Wing Val Lys Lys Wing Lys Arg Arg Asn Val 35 40 45 Gly Phe Glu Ser Asp Ser Gly Gly Wing Phe Lys Gly Phe Lys Gly Leu 50 55 60 Val Val Pro Ser Gly Gly Gly Gly Phe Ser Gly Phe Gly Gly Ser Gly 65 70 75 80 Gly Lys Pro Leu Glu Gly Leu Thr Asn Gly Asn Ser Thr Asp Asn Wing 85 90 95 Thr Pro Phe Ser Asn Val Lys Thr Wing Wing Glu Pro Lys Wing Wing Phe 100 105 110 Gly Ser Phe Wing Val Asn sly Pro Phe Thr Wing Glu Lys Lys Ser Asp 115 120 125 Wing Wing Gln Gly Wing Thr Ser Wing Being Phe Ser Phe Gly Lys Lys He 130 135 140 Glu Be Wing Wing Leu Gly be Leu Ser Gly Ser Leu Thr Gly Phe 145 150 155 160 Being Phe Being Wing Gly Being Ser Being Leu Phe Gly Lys Asp Wing Wing Gln 165 170 175 Ser Lys Wing Wing Ser Ser Leu Phe Ser Wing Lys Wing Ser Glu Ser Pro 180 185 190 Wing Gly Gly Gly Being Ser Glu Cys Arg Asp Gly Glu Glu Glu Glu Asn 195 200 205 Asp Glu Pro Pro Lys Val Val Val Thr Val Val Glu Glu Glu Asp Ala 210 215 220 Phe Tyr Ser Lys Lys Cys Lys Leu Phe Tyr Lys Lys Asp Asn Glu Phe 225 230 235 240 Lys Glu Lys Gly Val Gly Thr Leu His Leu Lys Pro Thr Ala Thr Gln 245 250 255 Lys Thr Gln Leu Leu Val Arg Wing Asp Thr Asn Leu Gly Asn He Leu 260 265 270 Leu Asn Val Leu He Wing Pro Asn Met Pro Cys Thr Arg Thr Gly Lys 275 280 285 Asn Asn Val Leu He Val Cys Val Pro Asn Pro Pro Leu Asp Glu Lys 290 295 300 Gln Pro Thr Leu Pro Wing Thr Met Leu He Arg Val Lys Thr Ser Glu 305 310 315 320 Asp Ala Asp Glu Leu His Lys He Leu Leu Glu Lys Lys Asp Ala 325 330 335 (2) INFORMATION ABOUT SEQ ID NO: 27: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 310 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..310 (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 27: Met Ala Lys Arg Val Ala Glu Lys Glu Leu Thr Asp Arg Asn Trp Asp 1 5 10 15 Glu Glu Asp Glu Val Glu Glu Met Gly Thr Phe Ser Val Wing Ser Glu 20 25 30 Glu Val Met Lyß Asn Arg Ala Val Lys Lys Wing Lys Arg Arg Asn Val 35 40 45 Gly Phe Glu Ser Asp Ser Gly Gly Wing Phe Lys Gly Phe Lys Gly Leu 50 55 60 Val Val Pro Ser Gly Gly Gly Gly Phß Ser Gly Phe Gly Gly Ser Gly 65 70 75 80 Gly Lys Pro Leu Glu Gly Leu Thr Asn Gly Asn Ser Thr Asp Asn Wing 85 90 95 Thr Pro Phe Ser Asn Val Lys Thr Wing Wing Glu Pro Lys Wing Wing Phe 100 105 110 Gly Ser Phe Wing Val Asn Gly Pro Thr Thr Leu Val Asp Lys Val Ser 115 120 125 Asn Pro Lys Thr Asn Gly Asp Ser Asn Gln Pro Pro Ser Ser Gly Pro 130 135 140 Wing Being Thr Wing Cys Pro Gly Asn Wing Tyr His Lys Gln Leu Wing 145 150 155 160 Gly Leu Asn Cys Ser Val Arg Asp Trp He Val Lys His Val Asn He 165 170 175 Asn Pro Leu Cys Asp Leu Thr Pro He Phe Lys Asp Tyr Glu Arg Tyr 180 185 190 Leu Wing Thr He Glu Lys Gln Leu Glu Asn Gly Gly Gly Ser Ser 195 195 205 Glu Ser Gln Thr Asp Arg Wing Thr Wing Gly Met Glu Pro Pro Ser Leu 210 215 220 Phe Gly Ser Thr Lys Leu Gln Gln Glu Ser Pro Phe Ser Phe His Gly 225 230 235 240 Asn Lys Ala Glu Asp Thr Ser Glu Lys Val Glu Phe Thr Ala Glu Lys 245 250 255 Lys Ser Asp Wing Wing Gln Gly Wing Thr Ser Wing Being Phß Ser Phß Gly 260 265 270 Lys Lys He Glu Be Ser Wing Leu Gly Ser Leu Ser Ser Gly Ser Leu 275 280 285 Thr Gly Phe Ser Phe Ser Ala Gly Ser Ser Ser Leu Phe Gly Lys Asp 290 295 300 Ala Ala Glu Lys Glu Leu 305 310 (2) INFORMATION ABOUT SEQ ID NO: 28: (i) CHARACTERISTICS D? THE SEQUENCE: (A) LENGTH: 132 amino acids (B) TYPE: amino acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..132 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 28: Thr Thr Leu Val Asp Lys Val Ser Asn Pro Lys Thr Asn Gly Asp Ser 1 5 10 15 Asn Gln Pro Pro Ser Ser Gly Pro Wing Ser Thr Wing Cys Pro Gly 20 25 30 Asn Wing Tyr His Lys Gln Leu Wing Gly Leu Asn Cys Ser Val Arg Asp 35 40 45 Trp He Val Lys His Val Asn Thr Asn Pro Leu Cys Asp Leu Thr Pro 50 55 60 He Phe Lys Asp Tyr Glu Arg Tyr Leu Wing Thr He Glu Lys Gln Leu 65 70 75 80 Glu Asn Gly Gly Gly Being Ser Glu Being Gln Thr Asp Arg Wing Thr 85 90 95 Wing Gly Met Glu Pro Pro Ser Leu Phe Gly Ser Thr Lys Leu Gln Gln 100 105 110 Glu Ser Pro Phe Ser Phe His Gly Asn Lys Ala Glu Asp Thr Ser Glu 115 120 125 Lys Val Glu Phe 130 (2) INFORMATION ABOUT SEQ ID NO: 29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) ) CHAIN FORM: simple (D) TOPOLOGY: linear "" (ii) TYPE OF THE MOLECULE: DNA (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..22 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 29: AGAAAGCAAA GCGCAGAAAT GT 22 (2) INFORMATION ABOUT SEQ ID NO: 30: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..21 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 30: CAAATCCAGA AAAGCGTCCT C 21 (2) INFORMATION ABOUT SEQ ID NO: 31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..24 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 31: TGAAGAATAG AGCCATAAAG AAAG 24 (2) INFORMATION ABOUT SEQ ID NO: 32: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) i ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..21 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 32: AGAAAAGCGT CCTCCTCCAG A 21 (2) INFORMATION ABOUT SEQ ID NO: 33: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 24 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..24 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 33: TGAAGAATAG AGCCATAAAG AAAG 24 (2) INFORMATION ABOUT SEQ ID NO: 34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..22 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 34: AGCGCCACTA ACCAAATCCA GA 22 (2) INFORMATION ABOUT SEQ ID NO: 35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..22 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 35: AGAAAGCAAA GCGCAGAAAT GT 22 (2) INFORMATION ABOUT SEQ ID NO: 36: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..22 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 36: GAAAAGCGTC CTCCTCCAGA AG 22 (2) INFORMATION ABOUT SEQ ID NO: 37: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..22 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 37: GAAAGCAAAG CGCAGAAATG TT 22 (2) INFORMATION ABOUT SEQ ID NO: 38: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..21 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 38: CTCCAGCGCC ACTACCAAAT C 21 (2) INFORMATION ABOUT SEQ ID NO: 39: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) ) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..20 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 39: CCCGCACGGA GCAGTTCAAG 20 (2) INFORMATION ABOUT SEQ ID NO: 40: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..22 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 40: GCAGCGGCAG ATCCCAAGGT AG 22 (2) INFORMATION ABOUT SEQ ID NO: 41: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 17 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..17 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 41: GTCATCCTTT TTCTCCA 1 (2) INFORMATION ABOUT SEQ ID NO: 42: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) STRING FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) [ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..22 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 42: CGTTCTTATC GTCTCTGTGT TC 22 (2) INFORMATION ABOUT SEQ ID NO: 43: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid (C) STRING FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS ((AA)) NNOOMMBBRREE // CCLLAVE: exon (B) SITUATION: 1..19 .- - - - (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 43: GCATCCTTTT TCTCCAGTA 19 (2) INFORMATION ABOUT SEQ ID NO: 44: (i) SEQUENCE CHARACTERISTICS:?) LENGTH: 18 base pairs, B) TYPE: nucleic acid • C) CHAIN FORM: simple ID) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (i) CAR CHARACTERISTICS: A) NAME / KEY: exon B) SITUATION: 1..18 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 44: TGTTCCAAAT CCACCAAT 18 (2) INFORMATION ABOUT SEQ ID NO: 45: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 base pairs ÍB) TYPE: nucleic acid • C) CHAIN FORM: simple D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..19 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 45: GTCTGCATCC TCGCTGGTT 19 (2) INFORMATION ABOUT SEQ ID NO: 46: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS. (A) NAME / KEY: exon (B) SITUATION: 1..21 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 46: CGTTCTTATC GTCTGTGTTC C 21 (2) INFORMATION ABOUT SEQ ID NO: 47: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..18 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 47: TTTTACCCGA ATCAACAT 18 (2) INFORMATION ABOUT SEQ ID NO: 48: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) CHAIN FORM: simple (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: DNA (genomic) (ix) CHARACTERISTICS: (A) NAME / KEY: exon (B) SITUATION: 1..21 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 48: GTACGCGAAC AGGGAAGAAT A 21 (2) INFORMATION ABOUT SEQ ID NO: 49: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 212 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single chain (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..212 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 49: Arg Val Ser Asn Gly Ser Pro Ser Leu Glu Arg Met Asp Ala Arg Gln 1 5 10 15 Wing Asp His Pro Lys Pro Be Wing Cys Arg Asn Leu Phe Gly Pro Val 20 25 30 Asn His Gly Glu Leu Thr Arg Asp Leu Glu Lys His Cys Arg Asp Met 35 40 45 Glu Glu Wing Ser Gln Arg Lys Trp Asn Phe Asp Phe Gln Asn His Lys 50 55 60 Pro Leu Glu Gly Arg Tyr Glu Trp Gln Glu Val Glu Arg Gly Ser Leu 65 70 75 80 Pro Glu Phe Tyr Tyr Arg Pro Pro Arg Pro Pro Lys Ser Wing Cys Lys 85 90 95 Val Leu Wing Gln Glu Ser Gln Asp Val Ser Gly Ser Arg Gln Wing Val 100 105 110 Pro Leu He Gly Ser Gln Wing Asn Ser Glu Asp Arg His Leu Val Asp 115 120 125 Gln Met Pro Asp Being As Asn Asn Gln Wing Gly Leu Wing Glu Gln Cys 130 135 140 Pro Gly Met Arg Lys Arg Pro Wing Wing Glu Asp Ser Ser Ser Gln He 145 150 155 160 Lys Arg Ala Asn Arg Thr Glu Glu Asn Val Ser Asp Gly Ser Pro Asn 165 170 175 Wing Gly Thr Val Glu Gln Thr Pro Lys Lys Pro Gly Leu Arg Arg Gln 180 185 190 Thr Arg Val Asp Leu Gln Pro Ser Phe Arg Wing Asn Phe Leu Phe Met 195 200 205 He Phe He Lys (2) INFORMATION ABOUT SEQ ID NO: 50: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 183 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single chain (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..183 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 50: Met Asp Ala Arg Gln Ala Asp His Pro Lys Pro Be Ala Cys Arg Asn 1 5 10 15 Leu he Gly Pro Val Asn His Gly Glu Leu Thr Arg Asp Leu Glu Lys 20 25 30 His Cys Arg Asp Met Glu Glu Ala Ser Gln Arg Lys Trp Asn Phe Asp 35 40 45 Phe Gln Asn His Lys Pro Leu Glu Gly Arg Tyr Glu Trp Gln Glu Val 50 55 60 Glu Arg Gly Ser Leu Pro Glu Phe Tyr Tyr Arg Pro Pro Cys Pro Pro 65 70 75 80 Lys Ser Wing cys Lys val Leu Wing Gln Glu Ser Gln Asp Val Ser Gly 85 90 95 Ser Arg Gln Wing Val Pro Leu He Gly Ser Gln Wing Asn Ser Glu Asp 100 105 110 Arg His Leu Val Asp Gln Met Pro Asp Being As Asp Asn Gln Ala Gly 115 120 125 Leu Ala Glu Gln Cys Pro Gly Met Arg Lys Arg Pro Ala Ala Glu Asp 130 135 140 be Ser Gln He Lys Arg Ala Asn Arg Thr Glu Glu Asn Val Ser 145 150 155 160 Asp Gly Ser Pro Asn Wing Gly Thr Val Glu Gln Thr Pro Lys Lys Pro 165 170 175 Gly Leu Arg Arg Gln Thr Arg 180 (2) INFORMATION ABOUT SEQ ID NO: 51: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 199 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single-chain ( D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..199 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 51: Arg Val Ser Asn Gly Ser Pro Pro Glu Arg Met Asp Ala Arg Gln 1 5 10 15 Wing Asp His Pro Lys Pro Be Wing Cys Arg Asn Leu Phe Gly Pro Val 20 25 30 Asn His Gly Glu Leu Thr Arg Asp Leu Glu Lys His Cys Arg Asp Met 35 40 45 Glu Glu Wing Ser Gln His Lys Trp Asn Phe Asp Phe Gln Asn His Arg 50 55 60 Pro Leu Glu Gly Arg Tyr Glu Trp Gln slu Val Glu Arg Gly Ser Leu 65 70 75 80 Pro Glu Phe Tyr Tyr Arg Pro Pro Arg Pro Pro Lys Ser Wing Cys Lys 85 90 95 Val Leu Wing Gln Glu Ser Gln Aap Val Ser Gly Ser Arg Gln Wing Val 100 105 110 Pro Leu He Gly Ser Gln Wing Asn Ser Glu Asp Arg His Leu Val Asp 115 120 125 Gln Met Pro Asp Ser As Asn Asn Gln Wing Gly Leu Wing Glu Gln Cys 130 135 140 Pro Gly Met Arg Lys Arg Pro Wing Wing Glu Asp Ser Ser Ser Gln He 145 150 155 160 Lys Arg Ala Asn Arg Thr Glu Glu Asn Val Ser Asp Gly Ser Pro Asn 165 170 175 Wing Gly Thr Val Glu Gln Thr Pro Lys Lys Pro Gly Pro Arg Arg Gln 180 185 190 Thr Arg Val Asp Leu Gln Pro 195 (2) INFORMATION ABOUT SEQ ID NO: 52: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 199 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single chain (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..199 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 52: Arg Val Ser Asn Gly Ser Pro Ser Leu Glu Arg Met Asp Ala Arg Gl? 1 5 10 15 Wing Asp His Pro Lys Pro Be Wing Cys Arg Asn Leu Phe Gly Pro Val 20 25 30 Asn His Gly Glu Leu Thr Arg Asp Leu Glu Lys His Cys Arg Asp Met 35 40 45 Glu Glu Wing Ser Gln Arg Lys Trp Asn Phe Asp Phe Gln Asn His Lys 50 55 60 Pro Leu Glu Gly Arg Tyr Glu Trp Gln Glu Val Glu Arg Gly Ser Leu 65 70 75 80 Pro Glu Phe Tyr Tyr Gly Pro Pro Arg Pro Pro Lys Ser Wing Cys Lys 85 90 95 Val Leu Wing Gln Glu Ser Gln Asp Val Gly Gly Ser Arg Gln Wing Val 100 105 110 Pro Leu He Gly Ser Gln Wing Asn Ser Glu Asp Arg His Leu Val Asp 115 120 125 Gln Met Pro Asp Being Ser Asp Asn Gln Wing Gly Leu Wing Glu Gln Cys 130 135 140 Pro Gly Met Arg Lys Arg Pro Wing Wing Glu Asp Ser Ser Ser Gln He 145 150 155 160 Lys Arg Ala Asn Arg Thr Glu Glu Asn Val Ser Asp Gly Ser Pro Asn 165 170 175 Wing Gly Thr Val Glu Gln Thr Pro Lys Lys Pro Gly Leu Arg Arg Gln 180 185 190 Thr Arg Val Asp Leu Gln Pro 195 (2) INFORMATION ABOUT SEQ ID NO: 53: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 199 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single chain (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..199 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 53: Val Ser Asn Gly Ser Pro Ser Leu Glu Arg Met Asp Ala Arg Gln Ala 1 5 10 15 Asp His Pro Lys Pro Be Wing Cys Arg Asn Leu Phe Gly Pro Val Asn 20 25 30 His Gly Glu Leu Thr Arg Asp Leu Glu Lys His Cys Arg Asp Met Glu 35 40 45 Glu Ala Ser Gln Arg Lys Trp Asn Phe Asp Phe Gln Asn His Lys Pro 50 55 60 Leu Glu Gly Arg Tyr Glu Trp Gln Glu Val Glu Arg Gly Ser Leu Pro 65 70 75 80 Glu Phe Tyr Tyr Gly Pro Pro Arg Pro Pro Lys Ser Wing Cys Lys Val 85 90 95 Leu Ala Gln Glu Ser Gln Asp Val Ser Gly Ser Arg Gln Ala Val Pro 100 105 110 Leu He Gly Ser Gln Wing Asn Ser Glu Asp Arg His Leu Val Asp Gln 115 120 125 Met Pro Asp Ser As As Asn Gln Ala Gly Leu Ala Glu Gln Cys Pro 130 135 140 Gly Met Arg Lys Arg Pro Wing Wing Glu Asp Ser Ser Ser Gln He Lys 145 150 155 160 Arg Ala Asn Arg Thr Glu Glu Asn Val Ser Asp Gly Ser Pro Asn Ala 165 170 175 Gly Thr Val Giu Gln Thr Pro Lys Lys Pro Gly Leu Arg Arg Gln Thr 180 185 190 Arg Val Asp Leu Gln Pro Ser 195 (2) INFORMATION ABOUT SEQ ID NO: 54: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 220 amino acids' 3) TYPE: amino acid C) STRING OF CHAIN: single chain? D) 7CPOLOGY: linear (ii) TYPE OF MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..220 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 54 Asn Val Arg Val Ser Asn Gly Ser Pro Be Leu Glu Arg Met Asp Wing 1 m -ic Arg Gln Wing Asp His Pro Pro Be Wing Cys Arg Asn Leu Phe Gly Pro 20 25 30 Val Asn His Gly Glu Leu Thr Arg Asp Leu Glu Lys His Cys Arg Asp 35 40 45 Met Glu Glu Wing Gln Arg Lys Trp Asn Phe Asp Phe Gln Asn His 50 55 60 Lys Pro Leu Glu Gly Arg Tyr Glu Trp Gln Glu Val Glu Arg Gly Ser 65 70 75 80 Leu Pro Glu Phe Tyr Tyr Arg Pro Pro Arg Pro Pro Lys Ser Wing Cys 85 90 95 Lys Val Pro Wing Gln Glu Ser Gln Asp Val Ser Gly Ser Arg Gln Wing 100 105 110 Val Pro Leu He Gly Ser Gln Wing Asn Ser slu Asp Arg His Leu Val 115 120 125 Asp Gln Met Pro Asp Being Ser Asp Asn Gln Wing Gly Leu Wing Glu Gln 130 135 140 Cys Pro Gly Met Arg Lys Arg Pro Wing Wing Glu Asp Being Ser Gln 145 150 155 160 He Lys Arg Ala Asn Arg Thr Glu Glu Aen Val Ser Asp Gly Ser Pro 165 170 175 Asn Wing Gly Thr Val Glu Gln Thr Pro Lys Lys Pro Gly Leu Arg Arg 180 185 190 Gln Thr Arg Val Asp Leu Gln Pro Ser Phe Arg Wing Asn Phe Leu Phe 195 200 205 Met He Phe He He Lys Val He Lys Lys He Ser 210 215 220 (2) INFORMATION ABOUT SEQ ID NO: 55: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 183 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single-stranded ID) TOPOLOGY: linear ( ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..183 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 55: Met Asp Ala Arg Gln Ala Asp His Pro Lys Pro Be Ala Cys Arg Asn 1 5 10 15 Leu Phe Gly Pro Val Asn His Gly Glu Leu Thr Arg Asp Leu Glu Lys 20 25 30 His Cys Gln Asp Met Glu Glu Ala Ser Gln Arg Lys Trp Asn Phe Asp 35 40 45 Phe Gln Asn His Lys Pro Leu Glu Gly Arg Tyr Glu Trp Gln Glu Val 50 55 60 Glu Arg Gly Ser Leu Pro Glu Phe Tyr Tyr Arg Pro Pro Arg Pro Pro 65 70 75 80 Lys Ser Wing Cys Lys Val Leu Wing Gln Glu Ser Gln Asp Val Ser Gly 85 90 95 Ser Arg Gln Wing Val Pro Leu He Gly Ser Gln Wing Asn Ser Glu Asp 100 105 110 Arg His Leu Val Asp Gln Met Pro Asp Being As Asp Asn Gln Ala Gly 115 120 125 Leu Wing Glu Gln Cys Pro Gly Met Arg Lys Arg Pro Wing Wing Glu Asp 130 135 140 Being Ser Gln He Lys Arg Wing Asn Arg Thr Glu Glu Asn Val Ser 145 150 155 160 Asp Gly Ser Pro Asn Wing Gly Thr Val Glu Gln Thr Pro Lys Lys Pro 165 170 175 Gly Leu Arg Arg Gln Thr Arg 180 (2) INFORMATION ABOUT SEQ ID NO: 56: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 138 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single chain ( D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..138 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 56: Met Asp Ala Arg Gln Ala Asp His Pro Lys Pro Be Ala Cys Arg Asn 1 5 10 15 Leu Phe Gly Pro Val Asn His Gly Glu Leu Thr Arg Asp Leu Glu Lys 20 25 30 His Cys Arg Asp Met Glu Glu Wing Being Gln Arg Lys Trp Asn Phe Asp 35 40 45 P e Gln Asn His Lys Pro Leu Glu Gly Arg Tyr Glu Trp Gln Glu Val 50 55 60 Glu Arg Gly be Leu Pro Glu Phe Tyr Tyr Gly Pro Pro Arg Pro Pro 65 70 75 80 Lys Ser Ala Cys Lys Val Leu Ala Gln Glu Ser Gln Asp Val Ser Gly 85 90 95 Ser Arg Gln Ala Val j- > ro Leu He Gly Ser Gln Wing Asn Ser Glu Asp 100 105 110 Arg His Leu Val Asp Gln Met Pro Asp Ser Ser Asp Ser Gln Ala Gly 115 120 125 Leu Ala Glu Gln Cys Pro sly Met Arg Lys 130 135 (2) INFORMATION ABOUT SEQ ID NO: 57: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 197 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single chain (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: protein (ix) CHARACTERISTICS: (A) NAME / KEY: protein (B) SITUATION: 1..197 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 57: Met Ser Asn Val Arg Val Ser Asn Gly be Pro Ser Leu Glu Arg Met 1 5 10 15 Asp Ala Arg Gln Ala Asp His Pro Lys Pro Be Ala Cys Arg Asn Leu 20 25 30 Phe Gly Pro to Asn His Glu Glu Leu Thr Arg Asp Leu Glu Lys His 35 40 45 Cys Arg Asp Met Glu Glu Ala Ser Gln Arg Lys Trp Asn Phe Asp Phe 50 55 60 Gln Asn His Lys Pro Leu Glu Gly Arg Tyr Glu Trp Gln Glu Val Glu 65 70 75 80 Arg Gly Ser Leu Pro Glu Phe Tyr Tyr Arg Pro Pro Arg Pro Pro Lye 85 90 95 Be Ala Cys Lys Val Leu Ala Gln Glu Ser Gln Asp Val Ser Gly Ser 100 105 110 Arg Gln Ala Val Pro Leu lie Gly Ser Gln Wing Asn Ser Olu Asp Arg 115 120 125 His Leu Val Asp Gln Met Pro Asp Ser Ser Asp Asn Gln Ala Gly Leu 130 135 140 Wing Glu Gln Cys Pro Gly Met Arg Lys Arg Pro Wing Wing Glu Asp Ser 145 150 155 160 Ser Ser Gln Asn Lys Arg Wing Asn Arg Thr Glu Glu Asn Val Ser Asp 165 170 175 Gly Ser Pro Asn Wing Gly Thr Val Glu Gln Thr Pro Lys Lys Pro Gly 180 185 190 Leu Arg Arg Gln Thr 195

Claims (28)

1. Claims 1.- Artificial nucleic acid structure containing the following constituents: component a): an activation sequence for transcripr.ir. The component b) b): a gene for a transcription factor containing b-j_) an activation domain b2) a binding sequence for a b3 inhibitor) a binding domain for component DNA c): a Activation sequence, which is activated by binding of the expression product of cc: r .-- r. "= d and which induces the transcription of component d) component d) an effector gene
2. 2.- Artificial nucleic acid structure according to claim 1, characterized in that component a) is the same as component c)
3. 3. - Artificial nucleic acid structure according to claim 1 or 2, characterized in that component a) constitutes a nonspecific activatable promoter sequence, specific for cells , metabolically specific, specific for viruses and "/ or specific for cell cycles.
4. 4.- Artificial nucleic acid structure according to claim 3, characterized in that the component a) is selected from the group consisting of activated promoters in endothelial cells, peritoneal cells, pleural cells, epithelial cells of the skin, of the lungs, of the gastrointestinal tract, kidney and urinary efferent pathways, in muscle cells, in connective tissue cells, in blood-forming cells, in macrophages, in lymphocytes, in leukemia cells, in tumor cells or in cells of glla, sequences of virus promoters, such as HBV, HCV, HSV, HPV, EBV, HTLV, CMV or HIV. - - sequences of promoters or enhancers, activated by hypoxia, or specific activation sequences for a cell cycle of genes for cdc225C, cyclin A, cdc2,? 2F-1, B-Myb, DHFR and - ¿ec e ":: 3 r.icr for transcription factors that "srar-rT-r. z are activated in a manner dependent on cell proliferation, such as monomers or multimers of the Myc E box.
5. 5. Artificial nucleic acid structure according to one of claims 1 to 4, characterized in that the activation domain [bl component) of the component b)] is selected from the activation domains of the transcription factors spanning Oct-2, Spl, NFY, ITF-2, VP-16, c-Myc and CTF.
6. 6.- "The artificial nucleic acid according to one of the reiv rd-acicr.es 1 to 5, characterized in that the binding sequence for an inhibitor (b2) is selected from a group that covers proteins that they inhibit p27 and thereby suppress the inhibition of cell proliferation produced by the p27 protein.
7. 7.- Artificial nucleic acid structure according to one of claims 1 to 5, characterized in that the binding sequence for an inhibitor (b2) contains the amino acid sequence- of p! 63 according to Table 6 [SEQ ID NO. : 24] or parts of it.
8. 8.- Artificial nucleic acid structure according to claim 7, characterized in that the parts of the amino acid sequence of pl63 are selected from the group consisting of peptides with the amino acid sequences of positions 1 to 24 [SEQ ID NO. ..- 10], from positions 137 to 196 [SEQ ID NO. : 12], from positions 215 to 265 [SEQ ID NO. : 14], from positions 239 to 272 [SEQ ID NO. : 16], from positions 399 to 438 [SEQ ID NO. : 18] and from positions 307 to 469 [SEQ ID NO. : 20] referring to the numbering according to Table 6.
9. 9.- Artificial nucleic acid structure according to one of claims 1 to 5, characterized in that the binding sequence for an inhibitor (b2) is obtained by deletion of functional domains from of the protein according to claim 7, having been deleted from [SEQ ID NO. : 24] of Table 5 the binding domain to p27? or the domain of union to Ran.
10. 10.- Artificial nucleic acid structure according to claim 9, characterized in that after deletion of the p27 binding domain, a protein with the amino acid sequence according to Table 8 is presented [SEQ ID NO. : 26] 0 and in the case of deletion of the Ran binding domain, a protein with the amino acid sequence according to Table 9 is presented [SEQ ID NO. : 27].
11. 11.- Artificial nucleic acid structure according to an i- claims 1 to 5, characterized because? Binding sequence for an inhibitor (b2) can be obtained by deletion of all the amino acid sequences except the area of the p27 binding domain of the protein according to claim 2.
12. 12. - Artificial nucleic acid structure according to claim 11 , characterized in that the binding sequence for an inhibitor contains the amino acid sequence according to Table 10 [SEQ ID NO. : 28].
13. 13.- Artificial nucleic acid structure according to one of claims 1 to 5, characterized in that the binding sequence for an inhibitor (b2) is selected from the group consisting of the corresponding homologous protein of the inhibitor or of the parts corresponding to this one of another species other than mammalian animal or of a human being according to one of claims 6 to 12. 0
14. 14.- Artificial nucleic acid structure according to claim 13, characterized in that the amino acid sequence of the inhibitor is the homologous human from the pl63.
15. 15.- Artificial nucleic acid structure according to one of claims 1 to 14, characterized in that component c) contains at least one (binding) sequence DNA for the binding of component b) and is activated by this binding.
16. 16. The artificial nucleic acid structure according to claim 15, wherein the DNA binding sequence is selected from the group consisting of the binding sequence (5 '-CGGACAACTGTTGACCCG-3 *, £? Q ID :: < D .. * X for the Gal 4 protein, the binding sequence (5 '-TACTGTATGTACATACAGTA-3', SEQ ID NO: 2) for the LexA protein, the binding sequence (5 '-GAATTGTGAGCGCGCACAATTC-3, SEQ ID NO: 3) for the Lac I repressor protein, the 5 'binding sequence -TCGAGTTTACCACTCCCTATCAGTGATAGA-GAAAAGTGAAAG-3', SEQ ID NO. * 4) for the tetracycline repressor protein and the binding sequence ( 5 '-TAATGATGGGCG-3', SEQ ID NO .: 5) for the ZFHD-1 protein.
17. 17.- Artificial nucleic acid structure according to one of claims 16, characterized in that the effector gene (component d) is a gene that codes for an active substance, which is selected from the group consisting of cytokines, chemokines , growth factors, receptors for cytokines, chemokines or growth factors, proteins that act antiproliferately or cytostatically or apoptotically, antibodies, fragments of antibodies, angiogenesis inhibitors, peptide hormones, coagulation factors, inhibitory agents of the coagulation, fibrinolytic proteins, peptides or proteins that act on the blood circulation, proteins of the blood plasma and antigens of pathogens of infections or of cells or tumors, producing the selected antigen an immunological reaction.
18. 18.- Artificial nucleic acid structure according to one of claims 1 to 14, characterized in that when referring to the effector gene it is txata of a gene, which encodes an enzyme that transforms a precursor compound of a drug into a drug.
19. 19.- Artificial nucleic acid structure according to one of claims 14, characterized in that the effector gene is a gene, which encodes a fusion protein of a ligand and an active substance, or a fusion protein of a nucleic acid. ligand and an enzyme, the ligand being selected from a group comprising cytokines, growth factors, antibodies, antibody fragments, peptide hormones, mediators and cell adhesion molecules.
20. 20.- Artificial structure of nucleic acid according to one of the preceding claims, characterized in that the nucleic acid is a DNA.
21. 21. Artificial structure according to one of the preceding claims, characterized in that the artificial nucleic acid structure is introduced into a vector.
22. 22. - Artificial nucleic acid structure according to claim 21, characterized in that it is a plasmid vector.
23. 23. - Artificial nucleic acid structure according to claim 21, characterized in that it is a viral vector.
24. 24.- Artificial nucleic acid structure according to one of claims 1 to 23, characterized in that it is administered externally, perorally, intravesically, nasally, intrabronchially or to the gastrointestinal tract, or is injected into an organ, into a body cavity, in the musculature, subcutaneously or in the bloodstream, for the prophylaxis or therapy of a disease.
25. 25.- Isolated cell, characterized in that it contains an artificial nucleic acid structure according to one of claims 1 to 24.
26. 26.- Use of an artificial nucleic acid structure according to one of claims 1 to 24, or of a cell according to the invention. claim 25 for the preparation of a medicament for the treatment of a disease selected from the group consisting of infections, tumors, leukemias, autoimmune diseases, allergies, arthritis, inflammations, organ rejections, transplant reactions against host, coagulation diseases of blood, diseases of circulation, blood poverty (anemia), hormonal diseases and injuries of the central nervous system.
27. 27. Procedure for the preparation of the artificial nucleic acid structures according to one of claims 1 to 24, wherein the individual elements are linked together stepwise.
28. 28. Use of a cell according to claim 25, for the preparation of a medicament for the therapy of diseases according to claim 24, characterized perqué at least one cell is administered externally, r.traves cai, nasal, intrabronchial, oral or in the gastrointestinal tract, or injected into an organ, a body cavity, the musculature, subcutaneously or in the bloodstream for the prophylaxis or therapy of a disease.