WO2001000822A2 - cDNA-SEQUENZEN VON ZWEI INTERAKTOREN FANCIP2 UND FANCIP3 DES FANCONI-ANÄMIE-PROTEINS DER KOMPLEMENTATIONSGRUPPE A - Google Patents
cDNA-SEQUENZEN VON ZWEI INTERAKTOREN FANCIP2 UND FANCIP3 DES FANCONI-ANÄMIE-PROTEINS DER KOMPLEMENTATIONSGRUPPE A Download PDFInfo
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- WO2001000822A2 WO2001000822A2 PCT/EP2000/005878 EP0005878W WO0100822A2 WO 2001000822 A2 WO2001000822 A2 WO 2001000822A2 EP 0005878 W EP0005878 W EP 0005878W WO 0100822 A2 WO0100822 A2 WO 0100822A2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to the cDNAs of two interactors (FANCIP2 and FANCIP3) of the Fanconi anemia protein of complementation group A (FANCA) and the proteins encoded thereby.
- Other subjects include the corresponding genes, antibodies directed against the proteins, FANCIP2 or FANCIP3 transgenic organisms and cells, and the use of FANCIP2 or FANCIP3 for effector screening and the pharmaceutical use of the nucleic acids, the proteins and the antibodies.
- Fanconi anemia (hereinafter referred to as "FA") is an autosomal recessive hereditary disease that manifests itself clinically with symptoms such as progressive pancytopenia, congenital malformations and an increased risk of cancer (Glanz and Fraser, 1982). At least 15% of the FA- Patients develop myeloid leukaemias (Auerbach and Allen, 1991).
- FA cells are cytogenetic due to a hypersensitivity towards DNA cross-linking agents, e.g. Mitomycin C (MMC) and Diepoxybutan (DEB), characterized, which manifests itself in chromosome breaks and aberrations (Auerbach, 1993).
- MMC Mitomycin C
- DEB Diepoxybutan
- FA lymphocytes and fibroblasts show a delay or an arrest in the G2 phase of the cell cycle after treatment with MMC (Kubbies et al., 1985; Seyschab et al., 1995).
- MMC Mitomycin C
- DEB Diepoxybutan
- FA lymphocytes and fibroblasts show a delay or an arrest in the G2 phase of the cell cycle after treatment with MMC (Kubbies et al., 1985; Seyschab et al., 1995).
- increased sensitivity to oxygen can be observed in FA cells (Joenje et al., 1981; Schindler and Hoehn, 1988; Po
- the object of the present invention was to find interactors of the Fanconi anemia proteins FANCA and FANCC. Based on the FA pathogenesis as a model system for mechanisms for maintaining genetic stability, the aim was to identify components of a protein complex or a protein cascade that play a role in DNA repair, cell cycle regulation and / or oncogenesis.
- the present invention describes the identification of two cDNAs that are responsible for
- FANCIP Fanconi anemia protein interacting protein
- the FANCIP2 or FANCIP3 cDNA and the proteins encoded thereby, but also the corresponding genes and antibodies directed against the proteins are therefore suitable as diagnostic, therapeutic or preventive agents for diseases which are associated with DNA repair defects, cell cycle disorders, Cytopenias, tumorigenesis and / or tumor progression are associated. They can also serve as targets for effector screening procedures to develop new drugs for the treatment of the aforementioned diseases.
- the present invention relates to two nucleic acids, which
- nucleotide sequences shown or a protein-coding section thereof b) one of the sequences from a) nucleotide sequences corresponding to the degeneracy of the genetic code, c) a nucleotide sequence hybridizing with the sequences from a) and / or b) under stringent conditions or d) comprises sequences complementary to the sequences from a) and / or b).
- the nucleotide sequence for FANCIP2 shown in FIG. 1 contains an open reading frame which corresponds to a protein with a length of 408 amino acids.
- the amino acid sequence of this protein is shown in Fig. 2.
- the nucleotide sequence for FANCIP3 shown in FIG. 3 contains an open reading frame which corresponds to a protein with a length of 1117 amino acids.
- the amino acid sequence of this protein is shown in Fig. 4.
- Variants are possible for FANCIP2, which differ from one another by the presence or absence of an 18 bp or 45 bp sequence section (bold sections in FIG. 1).
- the sequence database "GenBank” at the "National Center for Biotechnology Information” (NCBI) contains two human cDNA sequences which largely correspond to the nucleotide sequence for FANCIP2 shown in FIG. 1.
- the first sequence with the accession number AF151813 was determined using a comparative proteomics approach (Lai et al., 2000) and contains a possible open reading frame which is intended to code for a protein called CGI-55, the biological function of which is not explained.
- the open reading frame differs from the open reading frame of the FANCIP2 sequence at three nucleotide positions, which leads to two differences in the deduced amino acid sequence.
- the 45 bp section mentioned above is missing.
- the second sequence with the accession number AL080119 was published after the FANCIP2 first registration and corresponds to FANCIP2, whereby both the 18 bp and the 45 bp section are missing. A biological function is also not described here.
- the FANCIP2 sequence shown here has a further 34 nucleotides at the ⁇ 'end.
- the EST database at the NCBI contains cDNA fragments which correspond to subregions of the nucleotide sequence shown in FIG. 1.
- Examples are 50 human ESTs with 94% to 100% homology: accession numbers AL042397, AW467413, AW247188, AI872327, AI859542, AW732223, AW276167, AW957122, AW103463, AI814716, BE019064, AA158242, AW967070, AA3145255, AW243816, AW085671, AL036093, AW409749, AA429442, AA211632, AI499075, BE046106, AA693961, AA456789, AA160534, AW246719, AA224150, AA160357, AW518167, AA160629, AA1513709309269, AA28138F9309, 12928 , AW408542, AA112544, AA232104, AA307167, AA129629, AW250602, AW440390 and AA101431.
- the sequences represent variants without deletion, with 45 bp deletion and with 18 bp and 45 bp deletion.
- the EST access numbers contain no information about a complete open reading frame or about a possible biological function.
- FANCIP3 there are two cDNA sequences in the "GenBank" sequence database at the NCBI, which correspond to part of the open reading frame of the nucleotide sequence shown in FIG. 3. The first sequence was published after the first registration of FANCIP3 under the accession number AL096751 and corresponds to the sequence indicated in FIG. 3 from nucleotide 1090. This region differs from the FANCIP3 sequence at 2 nucleotide positions and contains a 102 bp deletion. There is no explanation of the biological function under this access number.
- the second sequence under the accession number X98258 corresponds to the sequence mentioned in FIG. 3 from nucleotide 2967 over a range of 554 nucleotides 100%.
- This sequence is the part of a cDNA that codes for a so-called M-phase phosphoprotein 9 (MPP9).
- MPP9 M-phase phosphoprotein 9
- This protein was identified by expression cloning together with other M-phase phosphoproteins (Matsumoto-Taniura et al., 1996). A function in cell division not previously explained is suspected.
- MPP9 could be localized in the cell during the interphase in the Golgi apparatus and during the M phase of mitosis in the cytoplasm. The sizes 150 and 160 kDa were determined for MPP9 by immunoprecipitation.
- the calculated size of the FANCIP3 mentioned in FIG. 4 is 125 kDa.
- EST database at the NCBI there are further cDNA fragments which correspond to partial areas of the nucleotide sequence shown in FIG. 3. Examples include 23 human ESTs with 94% to 100% homology: accession numbers AA306650, AI650373, AI630343, AW449069, AA847224, AA833889, AI377129, AW905060, AA313182, AA830355, AA973835, AA504104, AI656864, AA47145, AA4714256, AA47142523 AW393430, AA626158, AW610204, AI867901, AA736979 and AA442623.
- the FANCIP3 cDNA sequence shown in FIG. 3 thus contains a complete open reading frame for the
- the present invention also includes nucleotide sequences Nucleotide sequences that hybridize with one of the aforementioned sequences.
- hybridization according to the present invention is used as in Sambrook et al. (1989) used.
- Nucleic acids according to the invention can be isolated from mammals according to known techniques using short sections of the nucleotide sequence shown in FIG. 1 or FIG. 3 as hybridization probes and / or primers according to known methods. Furthermore, nucleic acids according to the invention can also be produced by chemical synthesis, it being possible to use modified nucleotide building blocks (for example methylated or 2'-0-alkylated nucleotides or phosphorothioates) instead of the customary nucleotide building blocks. Nucleic acids consisting partially or entirely of modified nucleotide building blocks can be used, for example, as therapeutic agents, e.g. as antisense nucleic acids or as ribozymes.
- modified nucleotide building blocks for example methylated or 2'-0-alkylated nucleotides or phosphorothioates
- the present invention further relates to a vector which contains at least one copy of one of the nucleic acids according to the invention.
- This vector can be any prokaryotic or eukaryotic vector on which a DNA sequence according to the invention is located and / or which enables the expression of a nucleic acid according to the invention in a suitable host cell.
- prokaryotic vectors are chromosomal vectors, such as bacteriophages, and extrachromosomal vectors, such as circular plasmid vectors.
- eukaryotic vectors are yeast vectors or vectors suitable for higher cells, such as plasmid vectors or viral vectors.
- the invention also relates to a vector which preferably contains at least a 15 nucleotide long section of the sequences shown in FIG. 1 or FIG. 3.
- This section preferably has a nucleotide sequence which comes from the protein-coding region of the sequences shown in FIG. 1 or FIG. 3 or from a region which is essential for the expression of the protein.
- These nucleic acids are particularly suitable for the production of therapeutically usable antisense nucleic acids.
- the present invention includes proteins encoded by the above nucleic acids. These proteins have the amino acid sequence shown in FIG. 2 (SEQ ID Nos. 5-8) or FIG. 4 (SEQ ID NO. 10) or a homology of more than 60%, preferably more than 70%, to that in FIG. 2 or 4 shown amino acid sequence.
- the invention also relates to variants and fragments of the protein shown in FIGS. 2 and 4. Variants are understood to mean sequences which differ from the amino acid sequence shown in FIG. 2 or FIG. 4 by substitution, deletion and / or insertion of individual amino acids or short amino acid segments.
- This term also includes chemically modified polypeptides. This includes Polypeptides that are modified on the termini and / or on reactive amino acid side groups by acylation or amidation.
- the invention also relates to methods which lead to the production of the proteins according to the invention and comprise both the cultivation of appropriately transformed cells and the isolation of the proteins according to the invention.
- the invention further relates to the use of polypeptides according to the invention or fragments of these polypeptides as immunogens for the production of antibodies.
- Antibodies can be produced in a customary manner by immunizing experimental animals with the complete polypeptide or fragments thereof and then obtaining the resulting polyclonal antisera.
- Monoclonal antibodies can be produced by known methods.
- the present invention thus also includes antibodies against FANCIP2 or FANCIP3 or a variant thereof.
- the FANCIP2 or FANCIP3 encoded by the nucleic acids according to the invention can be used as a target for a targeted search for effectors.
- Substances which have an inhibitory or activating effect on proteins according to the invention are able to selectively influence the cell functions controlled by these proteins. Therefore, they can be used in the therapy of corresponding clinical pictures, such as cytopenias or tumors.
- the invention thus also relates to a method for identifying effectors of FANCIP2 or FANCIP3, in which cells which express the protein are brought into contact with various potential effector substances and the cells are subjected to changes, for example cell-activating, cell-inhibiting, cell-proliferative and / or cell genetic changes.
- the invention relates to pharmaceutically active effector substances determined in the above-mentioned manner.
- the present invention also relates to a pharmaceutical composition which contains nucleic acids, vectors, cells, polypeptides, antibodies and / or effector substances as indicated above as the active component and furthermore pharmaceutically customary excipients, auxiliaries and / or additives and optionally further active components may contain.
- the pharmaceutical composition which contains nucleic acids, vectors, cells, polypeptides, antibodies and / or effector substances as indicated above as the active component and furthermore pharmaceutically customary excipients, auxiliaries and / or additives and optionally further active components may contain.
- Composition can be used in particular for the diagnosis, therapy or prevention of diseases which are associated with DNA repair defects, cell cycle disorders, cytopenias, tumor genesis and / or tumor progression. This also applies to the diagnosis of a predisposition to such diseases in individuals, in particular in the diagnosis of a risk for cytopenias and / or tumor diseases. Furthermore, a targeted diagnosis of diseases is made possible which are directly or indirectly linked to changes in the activity of FANCIP2 or FANCIP3. These tests can be carried out with the help of specific nucleic acid probes for detection at the nucleic acid level, e.g. at the gene or transcript level, or with the help of antibodies against i-ANCIP2 or FANCIP3 for detection at the protein level.
- gene therapy treatment can be carried out which involves the transmission of a nucleic acid coding for the FANCIP2 or FANCIP3 by means of vectors, e.g. viral vectors, into the appropriate target tissue.
- vectors e.g. viral vectors
- the present invention also relates to a method for diagnosing the abovementioned diseases, in which a patient or a sample originating from a patient, for example a sample of a body fluid or a tissue, is brought into contact with a pharmaceutical composition according to the invention and the nucleotide sequence and / or the Expression of the nucleic acid according to the invention determined qualitatively or quantitatively.
- a pharmaceutical composition according to the invention and the nucleotide sequence and / or the Expression of the nucleic acid according to the invention determined qualitatively or quantitatively.
- These determination methods can be used, for example, at the nucleic acid level by using nucleic acid hybridization probes or via reverse transcription / PCR or at the protein level by antibodies according to cyto- or histochemical methods.
- the pharmaceutical composition can be used as a marker for the occurrence of cytopenias, tumors or other proliferation-associated diseases or as a predisposition for the pathophysiological changes mentioned.
- the present invention also relates to a method for the therapy or prevention of one of the aforementioned diseases, wherein the patient is administered a pharmaceutical composition according to the invention which contains the active component in an amount effective against the disease.
- a pharmaceutical composition according to the invention which contains the active component in an amount effective against the disease.
- pharmaceutical compositions which are suitable for therapeutic purposes are, for example, bispecific antibodies and antibody toxins or antibody-enzyme conjugates.
- Further preferred pharmaceutical compositions for therapeutic purposes are antisense nucleic acids, gene therapeutic vectors or effector substances, e.g. in the form of low molecular weight activators or inhibitors.
- the complete coding sequence of the FANCA protein was cloned into the vector pEG202 via the EcoRI interface in the reading frame with the region coding for the LexA DNA-binding domain.
- the vector pJG4-5 was used for the expression of the prey protein, which allows the construction of fusion proteins with the B42-transactivating domain.
- a HeLa cDNA library cloned into this vector as a fusion gene library was screened with the FANCA bait protein.
- the yeast strain EGY48 served as the host organism. A positive interaction was demonstrated by transcription activation of the LEU2 gene, resulting in growth of the yeasts on leucine-free medium.
- EGY48 cotransformed with pEG202FANCA and the B42 fusion library were pre-selected on leucine-containing medium to obtain both vectors and recorded.
- To search for interacting yeast clones aliquots were plated on leucine-free medium and incubated for 3 to 5 days at 30 ° C. A total of aliquots were screened for an amount of 1 x 10 6 transfectants. The dependence of the transcription activation of positive clones on the expression of the prey protein was checked on leucine-free glucose medium.
- the interactor plasmids were isolated after growing the yeast in glucose medium without tryptophan, electroporation of the nucleic acid isolate in the E. coli strain XLIblue (Stratagene) and plasmid preparation from the bacterial cells. To confirm the interactions, retransformations of the isolated prey
- the 573 'RACE Kit (Boehringer-Roche) was used to determine the 5' partial sequences which were still missing.
- the sequence-specific primers FANCIP2-SP1 (5'-CTT CGT TCA CGA GGT GGT CG-3 ') and FANCIP2-SP2 (5'-CTT CCA ACT CGT CTT ATT CC-3') were used for FANCIP2 and the sequence-specific primers for FANCIP3 FANCIP3-SP1 (5'-CAC ATG ACA CTC TTC AGG AG- 3 ') and FANCIP3-SP2 (5'-CCT TTG GGA ACA TCT ATG TGC-3') are used.
- the PCR products obtained were electrophoretically purified and directly sequenced using the above-mentioned primers FANCIP2-SP2 and FANCIP3-SP3.
- the affiliation of the nucleotide fragments obtained to the plasmid-inserted interactor fragments was confirmed in each case by overlapping sequence regions.
- the sequence information from the above-mentioned GenBank entry AL096751 was used to design a corresponding 3' primer.
- FANCIP2 and FANCIP3 cDNA sequences were amplified from the total cDNA using PCR and sequence-specific 5 'and 3' primers.
- the primers were FANCIP2-P (5'-GCC ACC ATC ATG CCT GGG C-3 ') and FANCIP2-M (5'-GCA TCC AGT TAA GCC AGA GC-3') or FANCIP3-P ( 5 "-GAA GCC TCT GAA GAT GAC ACG-3 ') and FANCIP3-M (5'-ATA ACT GGA ACA CTG ACT GGC-3').
- the PCR products were cloned via the Smal interface into the vector pUC19
- the inserted PCR products for FANCIP2 and FANCIP3 were completely sequenced from transformed E. coli cells after plasmid preparation, using additional internal FANCIP2- or FANCIP3-specific as well as external pUC19-specific primers.
- the result for the FANCIP2 cDNA was a 1471 nucleotide long sequence (FIG. 1) with a possible open reading frame of 1224 nucleotides or 408 codons.
- the open reading frame contains two sequence areas with 18 bp and 45 bp (bold sections in FIG. 1), which are present independently of one another may or may not.
- the FANCIP3 cDNA resulted in a 3580 nucleotide long sequence (FIG. 3) with a possible open reading frame of 3351 nucleotides or 1117 codons.
- NCBI National Center of Biotechnology Information
- SEQ ID NO. 9 a nucleotide sequence which contains an open reading frame coding for FANCIP3,
- Figure 9 shows the nucleic acid primers used for PCR amplification of the FANCIP3 open reading frame.
- the Fanconi anemia gene FANCF encodes a novel protein with homology to ROM. Nat. Genet. 24, 15-16
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EP00943885A EP1194547A2 (de) | 1999-06-29 | 2000-06-26 | cDNA-SEQUENZEN VON ZWEI INTERAKTOREN FANCIP2 UND FANCIP3 DES FANCONI-ANÄMIE-PROTEINS DER KOMPLEMENTATIONSGRUPPE A |
AU58198/00A AU5819800A (en) | 1999-06-29 | 2000-06-26 | Cdna sequences of two interacting fancip2 and fancip3 of the fanconi anemia complementation group a protein |
JP2001506815A JP2003503053A (ja) | 1999-06-29 | 2000-06-26 | ファンコーニ貧血相補群Aタンパク質の2相互作用子FANCIP2とFANCIP3のcDNA配列 |
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DE19929887.4 | 1999-06-29 | ||
DE19929887A DE19929887A1 (de) | 1999-06-29 | 1999-06-29 | cDNA-Sequenzen von zwei Interakoren FANCIP2 und FANCIP3 des Fanconi-Anämie-Proteins der Komplementationsgruppe A |
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WO1998014462A1 (en) * | 1996-10-04 | 1998-04-09 | Fanconi Anemia Research Fund, Inc. | cDNA FOR FANCONI ANEMIA COMPLEMENTATION GROUP A |
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1999
- 1999-06-29 DE DE19929887A patent/DE19929887A1/de not_active Ceased
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- 2000-06-26 JP JP2001506815A patent/JP2003503053A/ja active Pending
- 2000-06-26 EP EP00943885A patent/EP1194547A2/de not_active Withdrawn
- 2000-06-26 AU AU58198/00A patent/AU5819800A/en not_active Abandoned
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WO1998014462A1 (en) * | 1996-10-04 | 1998-04-09 | Fanconi Anemia Research Fund, Inc. | cDNA FOR FANCONI ANEMIA COMPLEMENTATION GROUP A |
Non-Patent Citations (5)
Title |
---|
DATABASE EMBL [Online] Entry AF151813, 1. Juni 1999 (1999-06-01) LIN W.-C.: "Homo sapiens CGI-55 protein mRNA, complete cds." Database accession no. AF151813 XP002159188 & LAI C.-H. ET AL.: "Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics" GENOME RESEARCH, Bd. 10, Nr. 5, 2000, Seiten 703-713, XP000929862 * |
DATABASE EMBL [Online] Entry HSMPP9, 8. Januar 1997 (1997-01-08) WESTENDORF J.M.: "H. sapiens mRNA for M-phase phosphoprotein, mpp9" Database accession no. X98258 XP002159189 & NAOKO MATSUMOTO-TANIURA ET AL.: "Identification of novel M phase phosphoproteins by expression cloning" MOLECULAR BIOLOGY OF THE CELL, Bd. 7, Nr. 9, September 1996 (1996-09), Seiten 1455-1469, XP000979479 * |
DATABASE SWALL [Online] Entry Q9Y4S3, 1. November 1999 (1999-11-01) WAMBUTT R. ET AL.: "Hypothetical 42.4 kDa protein" Database accession no. Q9Y4S3 XP002159190 * |
HOSHINO T ET AL: "Molecular chaperone GRP94 binds to the Fanconi anemia group C protein and regulates its intracellular expression." BLOOD, (1998 JUN 1) 91 (11) 4379-86. , XP002159187 * |
STANLEY FIELDS ET AL.: "A novel genetic system to detect protein-protein interactions" NATURE, Bd. 340, Nr. 6230, 1989, Seiten 245-246, XP000103144 LONDON GB in der Anmeldung erw{hnt * |
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WO2001000822A3 (de) | 2001-07-05 |
AU5819800A (en) | 2001-01-31 |
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