EP2162539A2 - Minor-spleissosom testsystem zur modulierung der zellteilung - Google Patents
Minor-spleissosom testsystem zur modulierung der zellteilungInfo
- Publication number
- EP2162539A2 EP2162539A2 EP08784526A EP08784526A EP2162539A2 EP 2162539 A2 EP2162539 A2 EP 2162539A2 EP 08784526 A EP08784526 A EP 08784526A EP 08784526 A EP08784526 A EP 08784526A EP 2162539 A2 EP2162539 A2 EP 2162539A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- mrna
- substance
- minor
- cell division
- uli
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6875—Nucleoproteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/323—Chemical structure of the sugar modified ring structure
- C12N2310/3233—Morpholino-type ring
Definitions
- Test system for modulating, inhibiting or activating, the cell division in eukaryotes containing at least one in vivo cellular system containing at least one spliceable pre-mRNA which contains at least one intron and whose splicing depends on at least one snRNA U12 or Uli or U ⁇ atac or U5 or U4atac and the pre-mRNA in (a) contains at least one splice site for U12 or Uli, in the presence of at least one substance of interest and a detectable signal is induced, optionally with further adjuvants.
- U1-U5 snRNPs consisting of several proteins and one small nuclear (sn) RNA (U1, U2, U4, U5 or U6)
- sn small nuclear
- U1-U5 snRNPs consisting of several proteins and one small nuclear (sn) RNA (U1, U2, U4, U5 or U6)
- minor "(or U12-type) spliceosomes thus distinguishing the major spliceosome (containing the Ul, U2, U4, U5 and U6 snRNPs ), which processes more than 99% of human introns, from the minor spliceosome, which processes a rare class of introns with special, highly conserved sequences near the intron ends and additionally has a different snRNP composition (Uli and U12 snRNPs instead of Ul and U2; and U4atac or U6atac instead of U4 and U6).
- a splice site splices the boundaries of exons and introns. Its sequence is "Major” (or U2). Type introns are poorly conserved, making prediction of the exons almost impossible only on the basis of the DNA sequence and represents a major challenge in bioinformatics. These sequences are specifically recognized by the spliceosomes and spliced out. Each intron has three sequence regions important for splicing processing: (1) the 5 'splice site, (2) the polypyrimidine tract with the branch point adenosine, and (3) the 3 1 splice site , A standard intron usually starts at the 5 'splice site with GU and ends at the 3' splice site mostly at AG.
- the sequence 5 'AT - 3' AC can occur, which is why they have also been referred to as AT-AC introns.
- the key features of "minor” (or U12-type) introns are the highly conserved sequences of the 5 'splice site (detected by Uli snRNA) and the branch point adenosine (recognized by U12 snRNA) and a polypyrimidine tract.
- the minor spliceosome removes the very rare class of "minor” (or U12-type) introns, which account for as much as 0.4% of all introns in humans (CB Bürge, RA Padgett, PA Sharp, Mol Cell 2, 773 (Dec. 1998), A. Levine, R. Durbin, Nucleic Acids Res 29, 4006 (Oct 1, 2001)
- this minor spliceosome contains specific snRNAs, namely Uli, U12, U4atac and U6atac ( AA Patel, JA Steitz, Nat Rev Mol Cell Biol 4, 960 (Dec, 2003).
- an in vitro transcription mRNA is generally first prepared using genetic constructs with portions of viral or cellular genes. Such mRNAs contain all the important structural elements necessary for the recognition of mRNA by the spliceosomes and the process of splicing. In general, the mRNA is radiolabeled so that, after separation by means of a denaturing urea-polyacrylamide gel, the specific band pattern can be assessed with regard to the splicing reaction that has taken place.
- test systems are not suitable for all mRNAs and very time consuming and laborious. They are therefore not suitable for the systematic detection of substances that can modulate or even inhibit splicing.
- Further test systems for the major spliceosome are described in: WO00 / 52201 describes a gel-free in vitro detection system of a splicing reaction and the provision of appropriate probes.
- WO 01/79537 describes a homogeneous test system which is also gel-free.
- W001 / 7953 describes a cellular in vivo system which utilizes splittable nucleic acids with at least one intron and induces a detectable signal to find drugs. These test systems make no statement about the phenotypic design of the modulation in the organism.
- W000 / 75309 describes a spliceosomal protein associated with the U11 / U12 snRNP complex of the U12-dependent spliceosome specific for this spliceosome and its use in the diagnosis of disease.
- a test system for studying the function of the Ul2-dependent spliceosomes in the organism and consequent physiological processes dependent on this spliceosome (whose modulation can be used for the treatment of diseases) are not disclosed.
- a particular advantage of the present invention is therefore to provide a test system with which the function of the independent minor spliceosome in the physiological context of the intact organism, cellular in vivo system, can be investigated in an effective, specific and simple manner, and from it define dependent physiological processes that can be used to treat diseases.
- the essential role in cell division found here makes the minor spliceosome an interesting target for the effective treatment of diseases with out-of-control cell division.
- the invention therefore relates to a test system for modulating, inhibiting or activating, the cell division containing, a) at least one cellular in vivo system containing at least one spliceable pre-mRNA containing at least one intron, b) at least one snRNA U12 or Uli or U6atac or U5 or U4atac contains, c) wherein the pre-mRNA in (a) contains at least one splice site for U12 or Uli, d) in the presence of at least one substance of interest e) and a detectable signal is induced f) optionally further auxiliaries
- the in vivo cellular system is selected from eukaryotes.
- in vivo is understood to mean a reaction, ie a reaction, which takes place within a living cell.
- Cellular "in vivo" systems in the sense of the invention are spliceable eukaryotes preferably single as well as multicellular.
- cell lines from mammals - including human cell lines or yeasts or fish embryos or insect embryos, most preferably zebrafish embryos (zebrafish embryos (Danio rerio, formerly Brachydanio rerio) or fruit fly embryos (Drosophilidae).
- the signal according to (e) is morphologically and / or optically and / or biochemically detectable, such as by way of example and not limitation, the detection of BrdU (5'-bromo-2 x -deoxyuridine) BrdU is non-radioactive and can be administered in vivo after Incorporation into replicating DNA can be detected by means of monoclonal antibodies, immunohistochemically on tissue sections, whole embryos or cell cultures.
- fluorescently-labeled antibody eg antibodies against BrdU coupled with FITC (fluorescein isothiocyanate; RT-PCR for the detection of minor-class splicing) known proteins which induce an optical signal, as well as reporter molecules such as GFP (green fluorescent protein, protein from the jellyfish Aequorea victoria), or whose variants have other fluorescence spectra, for example CFP (cyan) or YFP (corresponding to the color).
- GFP green fluorescent protein, protein from the jellyfish Aequorea victoria
- CFP cyan
- YFP corresponding to the color
- eGFP enhanced GFP
- eYFP enhanced YFP
- fluorescent proteins from corals such as zoanFP (from Zoanthus sp.) or the red fluorescent protein drFP583 (from Discosoma ), Trade name DsRed, and others encoded by reporter genes, therefore, spliceable nucleic acids according to feature (a) and (c), which represent feature (a) and are preferred for a detek encode animal signal (s), but not selected from such Reportergenmolekülen.
- adjuvants according to feature (f) may be included, these adjuvants according to feature (f) are not conclusively selected from ATP, antibiotics e.g. Tertracycline, glucose and other adjuvants.
- Nucleic acids are composed of bases, phosphate groups, as well as the sugars deoxyribose (DNA) or ribose (RNA). They are carriers of genetic information.
- Nucleotides are the building blocks of the nucleic acids DNA and RNA. Each nucleotide consists of a base (purine or pyrimidine), a sugar molecule (deoxyribose or ribose) and a phosphate group. Through bonds, the nucleotides are linked together to chains. Oligonucleotides are short nucleic acid fragments with only a few nucleotides. You have the option of complementary mating with the DNA or RNA.
- RNA (English: ribonucleic acid) is a molecular chain composed of nucleotides. Certain types of this ribonucleic acid perform the task of transferring information from the genes to the ribosomes in cells.
- mRNA is the messenger RNA molecule, which is transcribed as a copy of the DNA's genetic information. The single-stranded mRNA transports the blueprint for the proteins to the ribosomes
- pre-mRNA refers to an intermediate that occurs in the translation of DNA into proteins in eukaryotes. It is the messenger ribonucleic acid mRNA immediately after its formation in the transcriptional phase of protein biosynthesis (protein synthesis), if it has not been processed.
- the pre-mRNA occurs as an intermediate in the first translation step, transcription: Not all DNA sections that are in a gene actually code for proteins, only the sections called exons.
- the enzyme RNA polymerase II copies the complete region of the DNA, including all introns, ie non-protein coding sections.
- the product is referred to as pre-mRNA.
- RNA sequence resulting from the splicing of the pre-mRNA is called mRNA.
- the pre-mRNA is modified by attaching a cap structure (at the 5 'end), a poly (A) tail, and splicing the introns in the nucleus. This happens in part already during the transcrip- tion.
- the finished processed RNA is called mature mRNA. This is transported to the cytoplasm where translation begins.
- siRNA small interfering RNA
- siRNA small interfering RNA is a specific class of RNA designed to selectively inhibit the translation of certain mRNAs.
- Spliceosome is a large aggregate of snRNA and snRNP molecules that perform pre-mRNA splicing in a eukaryotic cell.
- the individual components pre-mRNA, snRNPs and snRNA
- SnRNAs small nuclear RNA
- SnRNAs are RNA molecules that are complexed with proteins to form the ribonucleoprotein particles involved in RNA splicing.
- SnRNAs are about 100 to 300 base pair RNAs. These are catalytically active RNAs in the nucleus of eukaryotes.
- snRNPs small nuclear ribonucleoproteins
- snRNPs small nuclear ribonucleoproteins
- RNA splicing a process by which intron sequences from RNA transcripts in the nucleus are excised to produce the mRNA and other RNAs.
- Morpholinos or Morpholino Oligos are nucleic acids that are used as tools in genetics to achieve knockdown of genes. These are synthetic molecules that are produced by structurally modified nucleic acid building blocks and are also called PMOs (phosphorodiamidate morpholino oligo). They are used in antisense RNA experiments and inhibit by binding to the complementary mRNA either the translation or splicing of the pre-mRNA and thus the formation of a protein. Their mode of action is thus comparable to the siRNAs, but Morpholinos have a higher stability and thus longer half-life, as they do not represent RNAse substrates. The disadvantage, however, is that a transfection of morpholinos is difficult, so it is usually resorting to injection
- a thus (Germanized Latin von thusus) is a so-called Ursegment (Urwirbel), which occurs temporarily in the embryonic development of vertebrates.
- the somites are pinched in the head-foot direction (craniocaudal) from the mesoderra to the side of the midline (paraxial). They are therefore located in two strands right and left of the axial structures Chorda dorsalis and Neuralrohr.
- the ventromedial part is called mesenchymal and as a sclerotome.
- the dorsolateral (lateral), epithelial portion is called the dermatomyotoma.
- SEQ ID No.1 represents a nucleic acid sequence for the U12 snRNA (human), NCBI Accession J04119.
- SEQ ID no. Figure 2 depicts a nucleic acid sequence for the U ⁇ atac snRNA (human), NCBI Accession U62823, NCBI Accession JO4119.
- SEQ ID no. Figure 3 depicts a nucleic acid sequence for the U4atac snRNA (human), NCBI Accession 62822.
- SEQ ID no. Figure 4 depicts a nucleic acid sequence for Uli snRNA (human), NCBI Accession JO4118.
- the inventive method for finding an effective substance for inhibiting cell division using a test system characterized in that the substance according to feature (d) affects the pre-mRNA splicing of the minor spliceosomes inhibited or activated.
- the pre-mRNA splicing by modulating the respective recognition sequence ( Figure 1) between the snRNAs of the minor spliceosome U12 or Uli with the pre-mRNA according to feature (c), or the respective recognition sequence between U6atac or U4atac, or respective recognition sequence between U6atac and U12.
- active substance is selected from natural substances in the broadest sense, combinatorial substance libraries, pharmaceuticals, insecticides, herbicides, pesticides, nucleic acid oligomers, antibodies. This may be a naturally occurring, naturally occurring and chemically modified and / or synthetic substance.
- the method according to the invention for selectively inhibiting the function of splicing ⁇ osome-specific snRNAs have been developed.
- One embodiment is inhibition with synthetic nucleic acid oligomers, so-called morpholino oligomers (morpholinos), that specifically bind to snRNAs and sequester sequences that mediate interaction with sequence elements in the pre-mRNA and with other snRNAs snRNAs.
- Preferred morpholino oligomers having the nucleic acid sequence SEQ ID No.5 ttgaatactcattccttttattgct-5 '(U12-morpholino) or SEQ ID No.6 cacaacatactctctctctttakaa-5 (U6atac-morpholino) or variations (structural relatedness) of said aforementioned nucleic acid sequences having a sequence homology ( complementary nucleic acid bases) of at least 70 percent in the Northern Blot.
- FIG. 2A BrdU incorporation into control morpholino-injected (cMO) and U12-morpholino-injected (ul2M0) zebrafish embryos.
- Figure 2B Detection of mitotic cells in embryos treated as described in Figure 2A using anti-phospho-histone H3 / Cy3 antibody staining.
- a method of diagnosing a disease characterized in that at least one cellular in vivo system containing at least one spliceable pre-mRNA and at least one snRNA U12 or Uli or U ⁇ atac or U5 or U4atac, in the presence of at least one substance of interest and optionally further adjuvants and that the modulation of cell division is detected.
- the disease is a tumor disease (cancer) or hereditary disease.
- the present invention is not only a test system, screening system, for substances but also a method for measuring the minor spliceosome activity and its specific elimination.
- the interference with the minor spliceosome in the organism and the elucidation of the role of the minor esophagosome in cell proliferation provides the basis for finding substances that encode the minor spliceosome and inhibit cell division.
- the function of the minor esophagosome in the control of cell division is disease-relevant (eg cancer) and can be modulated with substances that influence the minor spliceosome in cells and in the organism.
- the essential point is therefore also the possibility of simple, effective and specific inhibition of the minor spliceosome in cells or in the organism (eg zebrafish) and thus the definition of the specific role of the minor spliceosome in the organism.
- Fertilized zebrafish eggs (without chorion) were injected with 0.5 ⁇ l morpholino solution against U12 snRNA (0.0ImM; TCGTTATTTTCCTTACTCATCAGTT) or a solution of a corresponding morpholino with 5 mismatch nucleotides (0.ImM; TCGTGATTTGCCTTCCTCAGCAGTG) as control.
- BrdU-incorporating cells markers for DNA synthesis, S-phase
- human breast cancer cell lines are arrested in the cell division cycle.
- a morpholino was introduced against Ul2 snRNA (TCGTTATTTTCCTTACTCATAAGTT) or a standard control morpholino (CCTCTTACCTCAGTTACAATTTATA).
- Ul2 snRNA TCGTTATTTTCCTTACTCATAAGTT
- CCTCTTACCTCAGTTACAATTTATA a standard control morpholino
- 2x107 cells were electroporated with 20 ⁇ l of a 0.5 mM morpholino solution in 350 ⁇ l PBS. After 24 h the cells were fixed, the DNA stained with DRAQ 5 and the DNA profile was examined by flow cytometry.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE200710031574 DE102007031574B4 (de) | 2007-07-06 | 2007-07-06 | Minor-Spleißosom Testsystem zur Modulierung der Zellteilung |
PCT/EP2008/004972 WO2009006990A2 (de) | 2007-07-06 | 2008-06-20 | Minor-spleissosom testsystem zur modulierung der zellteilung |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2162539A2 true EP2162539A2 (de) | 2010-03-17 |
Family
ID=40092515
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP08784526A Withdrawn EP2162539A2 (de) | 2007-07-06 | 2008-06-20 | Minor-spleissosom testsystem zur modulierung der zellteilung |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP2162539A2 (de) |
DE (1) | DE102007031574B4 (de) |
WO (1) | WO2009006990A2 (de) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102220416B (zh) * | 2011-04-20 | 2013-01-23 | 北京师范大学 | 一种监测细胞***次数的方法及其应用 |
WO2016111216A1 (ja) * | 2015-01-05 | 2016-07-14 | 国立大学法人九州大学 | 有機エレクトロルミネッセンス素子、有機エレクトロルミネッセンス素子の駆動方法および照明装置 |
WO2023021073A1 (en) * | 2021-08-17 | 2023-02-23 | Universität Bern | Minor spliceosome targeting compositions and their use in cancer treatment |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19909156A1 (de) | 1999-03-02 | 2000-09-07 | Aventis Res & Tech Gmbh & Co | Testsystem zum Nachweis einer Spleißreaktion, sowie dessen Verwendung |
DE19925668A1 (de) | 1999-06-04 | 2001-03-15 | Aventis Res & Tech Gmbh & Co | Spleißosomprotein und seine Verwendung |
US6137936A (en) | 1999-07-22 | 2000-10-24 | Pirelli Cables And Systems Llc | Optical fiber cable with single strength member in cable outer jacket |
DE10018465A1 (de) | 2000-04-14 | 2001-10-18 | Aventis Res & Tech Gmbh & Co | Testsystem zum Nachweis einer Spleißreaktion, sowie dessen Verwendung |
-
2007
- 2007-07-06 DE DE200710031574 patent/DE102007031574B4/de not_active Expired - Fee Related
-
2008
- 2008-06-20 WO PCT/EP2008/004972 patent/WO2009006990A2/de active Application Filing
- 2008-06-20 EP EP08784526A patent/EP2162539A2/de not_active Withdrawn
Non-Patent Citations (1)
Title |
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See references of WO2009006990A3 * |
Also Published As
Publication number | Publication date |
---|---|
WO2009006990A2 (de) | 2009-01-15 |
DE102007031574B4 (de) | 2012-01-26 |
WO2009006990A3 (de) | 2009-04-02 |
DE102007031574A1 (de) | 2009-01-08 |
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