EP1515742A2 - Genes impliques dans la regulation de l angiogenese, preparations pharmaceutiques les contenant et leurs applications. - Google Patents
Genes impliques dans la regulation de l angiogenese, preparations pharmaceutiques les contenant et leurs applications.Info
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- EP1515742A2 EP1515742A2 EP03727567A EP03727567A EP1515742A2 EP 1515742 A2 EP1515742 A2 EP 1515742A2 EP 03727567 A EP03727567 A EP 03727567A EP 03727567 A EP03727567 A EP 03727567A EP 1515742 A2 EP1515742 A2 EP 1515742A2
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Definitions
- the present invention belongs to the field of pharmaceutical compositions useful for the treatment of pathologies resulting from a deregulation of the mechanism of angiogenesis.
- the amplified DNA is ligated into the plasmid which is transformed into the bacterium according to the method described by Sambrook et al. (1989, Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.).
- the transformed cells are spread on LB agar medium containing the antibiotics, the antibiotic resistant colonies are then checked by PCR then analysis on gel. Plasmid DNA can be isolated and then sequenced to confirm the construction.
- the production and purification of the recombinant protein can be carried out as described ((Patry et al, 1994, FEBS Lett, 349 (1): 23-8), 473- 480). Briefly, an isolated colony is inoculated into the medium.
- the recombinant protein can be produced for example in the yeast Pichia Pastoris as described by Sreekrishna et al (1988, J Basic Microbiol, 28 (4): 265-78).
- the amplified DNA will be introduced in the same way after digestion and ligation in a Pichia Pastoris expression vector, preferably containing a sequence coding for a selection marker (Scorer et al, Biotechnology (NY), 1994 Feb; 12 ( 2): 181-4).
- the present invention also relates to a method for the diagnosis and prognosis of an angiogenic pathology in a mammal, in particular in a human being, comprising detecting in the cells of said mammal the overexpression or under-expression of one or more identified polypeptide sequences. by the SEQ ID No.: 54 to SEQ ID No.: 102 or with the polypeptide sequences identified under the numbers SEQ ID No.: 291 to SEQ ID No.: 297 in the attached sequence list.
- said method comprises the following steps: a) detecting the expression of one or more of said polypeptide sequences SEQ ID No.: 54 to SEQ ID No.: 102 or with the polypeptide sequences identified under the numbers SEQ ID No.: 291 to SEQ ID No.: 297 by a cell population of a mammal, b) detecting the expression of that (s) same (s) sequence (s) polypeptide (s) ) by a reference cell population of which the angiogenic state is known, c) the identification of possible differences in the level of expression of that same polypeptide sequence (s) by the two cell populations .
- the verification method is carried out on a cell population of a mammal in vivo, ex-vivo, or else on a cell population isolated from said mammal in vitro.
- vascularization of tumors capable of being diagnosed or treated with the pharmaceutical compositions of the invention, there may be mentioned: vascularization of tumors, retinopathies, rheumatoid arthritis, Crohn's disease, atherosclerosis, hyperstimulation of ovary, psoriasis, endometria associated with neovascularization, restenosis due to balloon angioplasty, tissue overproduction due to scarring, peripheral vascular disease, hypertension, vascular inflammation, disease and Raynaud's phenomena, aneurysm, arterial restenosis, thrombophlebitis, lymphagyte, lymphodema, scarring and tissue repair, ischemia, angina, myocardial infarction, chronic heart disease, heart failure such as congestive heart failure, age-related acular degeneration and osteoporosis.
- the subject of the invention is also a device comprising a support comprising one or more probes specific for one or more nucleotide sequences identified under the numbers SEQ ID No: 1 to SEQ ID No: 53, SEQ ID No. 225 and SEQ ID No 284 to SEQ ID No. 290, in the sequence list in the appendix for the implementation of the screening method of the invention.
- FIG. 1 shows that the expression of GS-V1, GS-V2, GS-V4, GS-V5, GS-V15 in human endothelial cells inhibits the formation of capillary tubes: endothelial cells transfected with 1A) GS-Vl encoding for the GS-N1 specific antisense transcript; 1B) GS-V2 coding for the GS-N2 specific antisense transcript; 1C) GS-V4 encoding the GS-N4 specific antisense transcript; 1D) GS-V5 coding for the GS-N5 specific antisense transcript; 1E) GS-V15 encoding the specific GS-N15 antisense transcript; 2F) the empty vector (Control).
- FIG. 2 shows that the expression of GS-V3, GS-V14 in human endothelial cells inhibits the formation of capillary tubes: endothelial cells transfected with 2A) GS-V3 coding for the antisense transcript specific for GS-N3; 2B) GS-V13 encoding the specific antisense transcript of GS-N13; 2C) the empty vector (Control).
- FIG. 2 shows that the expression of GS-V3, GS-V14 in human endothelial cells inhibits the formation of capillary tubes: endothelial cells transfected with 2A) GS-V3 coding for the antisense transcript specific for GS-N3; 2B) GS-V13 encoding the specific antisense transcript of GS-N13; 2C) the empty vector (Control).
- 3 shows that the expression of GS-V6, GS-V8, GS-V10 in human endothelial cells induces the formation of capillary tubes: transfected endothelial cells where 3A) GS-V6 coding for the GS-specific antisense transcript N6; 3B) GS-V8 encoding the specific GS-N8 antisense transcript; 3C) GS-V10 encoding the specific antisense transcript of GS-N10 and its homolog GS-N54; 3D) the empty vector (Control).
- FIG. 4 shows that the expression of GS-V7, GS-V9, GS-V11, GS-V12, GS-V14 in human endothelial cells inhibits the formation of capillary tubes: endothelial cells transfected with 4A) GS-V7 encoding for the specific antisense transcript of GS-N7; 4B) GS-V9 encoding the GS-N9 specific antisense transcript; 4C) GS-Vl1 coding for the GS-N11 specific antisense transcript; 4D) GS-V12 encoding the specific antisense transcript of GS-N12; 4E) GS-V14 coding for the specific antisense transcript of GS-N14 and 4F) the empty vector (Control).
- FIG. 6 shows that the expression of GS-V22, GS-V24, GS-V25, GS-V26, GS-V27 in human endothelial cells inhibits the formation of capillary tubes: endothelial cells transfected with 6A) GS-V22 encoding for the specific antisense transcript of GS-N22; 6B) GS-V24 encoding the antisense transcript specific for GS-N24 and its GS-N49 counterpart; 6C) GS-V25 coding for the specific antisense transcript of GS-N25 and of its homolog GS-N50; 6D) GS-V26 encoding the specific GS-N26 antisense transcript; 6EJGS-V27 encoding the specific antisense transcript of GS-N27 and its homolog GS-N51; 6F) the empty vector (Control).
- FIG. 9 shows that the expression of GS-V40, GS-V42, GS-V43, GS-V44, GS-V45 in human endothelial cells inhibits the formation of capillary tubes: endothelial cells transfected with 9A) GS-V40 encoding for the specific antisense transcript of GS-N40; 9B) GS-V42 encoding the specific antisense transcript of GS-N42; 9C) GS-V43 encoding the specific antisense transcript of.GS-N43; 9D) GS-V44 encoding the specific antisense transcript of GS-N44; 9E) GS-V45 coding for the specific antisense transcript of GS-N45; F) the empty vector (Control).
- the cells are firstly seeded on a type I Collagen gel in complete medium until confluence. Then, the reference HUVEC cells are cultured in a medium depleted in serum and without growth factors: EBM-2 + 2% serum and various factors are added under the test conditions.
- TNF- at concentrations between 20 ng / ml and 100 ng / ml, preferably between 30 ng / ml and 60 ng / ml
- IFN- ⁇ at concentrations between 50 ng / ml and 200 ng / ml, preferably between 80 ng / ml and 120 ng / ml.
- Human endothelial cells placed under the four aforementioned culture conditions are then used to identify genes coding for the cellular constituents involved in the regulation of angiogenesis.
- Angiogenic and angiostatic factors having an effect on the expression of the genes identified in correlation with the formation of new vessels or the inhibition of new vessels respectively, used, by way of example, in the context of the present invention, are illustrated below. -Dessous.
- VEGF ⁇ Vascular endothelial growth factor VEGF ⁇ Vascular endothelial growth factor
- FGF2 Basic fibroblast growth factor
- Gene expressions can then be compared using DNA chips, SAGE, an amplification reaction by quantitative PCR, viral vectors to build subtractive libraries, or even differential display analysis.
- the Applicant preferentially used the differential display technique for the identification of said genes.
- the total RNAs are prepared from HUVEC cells cultured on a collagen gel in the presence of the various factors used, according to the RNeasy Mini kit method (Qiagen) by integrating a DNase I digestion step according to the protocol recommended by the manufacturer.
- the differential display from total RNAs is carried out according to the method described by Liang and Pardee (1992, Science, 14; 257 (5072): 967-7) using P33-ATP in isotopic dilution during the PCR amplification for the visualization of the bands by autoradiography of the electrophoresis gels.
- primers contain at each of their ends, a site of a different restriction enzyme (Sali: GTCGAC or MluI: ACGCGT).
- restriction sites can be interchanged depending on whether the fragment has been cloned into the bacterial plasmid in its sense or antisense orientation.
- Each vector comprising said antisense fragment is then produced in E.Coli, extracted, purified and quantified.
- One ⁇ g of each vector is incubated in the presence of a transfecting agent (effectene, Qiagen) following the protocol recommended by the manufacturer with endothelial cells. Twenty-four hours after transfection, the endothelial cells are trypsinized and spread on the extracellular matrix containing the angiogenic factors in this case the matrigel according to the model described by Grant et al, (1989, Cell, 58 (5): 933- 43). After 24 hours of incubation, the formation of vessels is observed and compared to control cells transfected with the empty mammalian expression vector.
- a transfecting agent effectene, Qiagen
- the expression systems can comprise an antibiotic selection marker (an antibiotic resistance gene), for selecting the transfected cells stably expressing the vector comprising the nucleic acid cloned in said vector and this, either in the same vector or in a vector cotransfected 2nd.
- an antibiotic selection marker an antibiotic resistance gene
- the stable lines for the expression of the antisense oligonucleotide corresponding to each identified gene were obtained with a constitutive expression vector and after selection in the presence of antibiotic.
- the sequence of this mRNA has a coding sequence from nucleotide 159 to nucleotide 458.
- a GS-P1 protein resulting from the translation of this mRNA.
- This protein is composed of 99aa, identified under the number SEQ ID No 54 in the attached sequence list, called Angioinducin - GS-N2; a 1649 bp mRNA, identified by the sequence SEQ ID No: 2 in the annexed sequence list.
- BLAST search on the basis of sequences
- This mRNA has a partial coding sequence from nucleotide 1 to nucleotide 4762.
- GS-P4 protein resulting from the translation of this mRNA.
- This protein is composed of 1586 aa, identified under the number SEQ ID No 57 in the attached sequence list, called Angioreceptin
- the sequence of this mRNA has a coding sequence from nucleotide 90 to nucleotide 773.
- GS-P6 a protein GS-P6, resulting from the translation of this mRNA.
- This protein is composed of 227 aa, identified under the number SEQ ID No 59 in the attached sequence list, called Vassoserpentine.
- - GS-N7 an mRNA of 4397 identified by the sequence SEQ ID No: 7 in the list of sequences in the appendix. BLAST search on the basis of sequences
- the sequence of this mRNA has a partial coding sequence from nucleotide 286 to nucleotide 2943.
- a protein GS-P7 resulting from the translation of this mRNA.
- This protein is composed of 885 aa, identified under the number SEQ ID No 60 in the attached sequence list, called Angiosulfatin.
- - GS-N8 an mRNA of 5844 bp identified by the sequence SEQ ID No: 8 in the list of sequences in the appendix.
- BLAST search on the basis of sequences GENBANK allows to identify it under the accession number
- the sequence of this mRNA has a partial coding sequence from nucleotide 1 to nucleotide 3456.
- GS-P8 protein resulting from the translation of this mRNA.
- This protein is composed of 1151 aa, identified under the number SEQ ID No 61 in the attached sequence list, called Vassoreceptin.
- the sequence of this mRNA has a partial coding sequence from nucleotide 1 to nucleotide 3528.
- GS-P9 protein resulting from the translation of this mRNA.
- This protein is composed of 1175 aa, identified under the number SEQ ID No 62 in the attached sequence list, called Angiokinasine.
- Angiokinasin is homologous with MAP4K4 (SEQ ID No.: 224 in the sequence list in the appendix), accession number: XM_038751 (Nucleic sequence: 4197 bp, protein sequence: 1141aa).
- T cells deficient in MAPK 4 show a decoupling of the production of IL-2 following activation of T cell receptors suggesting a key role for MAPK4 / JNK in the inflammatory process.
- the mutation of MAPK4 in certain carcinomas indicates that it can play a role in suppressing tumors.
- the control of the expression and the activity of MAPK4 are currently the subject of intense analyzes and studies, these are in an approach to develop an anti-inflammatory and anticancer therapy.
- the role of MAPK4 in angiogenesis has not been demonstrated to date.
- Pedram et al (Endocrinology, 2001, 142: 1578-86) have shown that the natriuretic peptide suppresses or inhibits VEGF-induced angiogenesis, and they also showed that the activation of kinases acting directly on the N-terminal of c-Jun is an important step in the induction of angiogenesis by VEGF.
- Jimenez et al, Oncogene, 2001, 20: 3443-3448 reported that activation of the kinases acting on the N-terminal of c-Jun is necessary for the inhibition of neovascularization by thrombospondin 1 .
- GS-N54 a 4749 bp mRNA identified by the sequence SEQ ID No: 16 in the annexed sequence list. BLAST search on the basis of sequences
- AK024248 This mRNA has no coding sequence.
- the GS-N10 mRNA sequence has a coding sequence from nucleotide 618 to nucleotide 1787.
- a protein GS-P10 resulting from the translation of this mRNA.
- This protein is composed of 389 aa, identified under the number SEQ ID No 63 in the attached sequence list, called Vassosubstratin.
- - GS-N12 a 4131bp mRNA identified by the sequence SEQ ID No: 12 in the annexed sequence list.
- a BLAST search on the GENBANK sequence base makes it possible to identify it under the accession number AB023233.
- - GS-N13 a 2566bp mRNA identified by the sequence SEQ ID No: 13 in the sequence list in the appendix.
- a BLAST search on the GENBANK sequence base makes it possible to identify it under the number XM_018273.
- the sequence of this mRNA has a coding sequence from nucleotide 426 to nucleotide 2345.
- a protein GS-P13 resulting from the translation of this mRNA.
- This protein is composed of 639 aa, identified under the number SEQ ID No 66 in the attached sequence list, called Angiohelicin.
- This sequence does not contain a coding sequence.
- - GS-N15 a 6253 bp mRNA identified by the sequence SEQ ID No: 15 in the sequence list in the appendix.
- a BLAST search on the GENBANK sequence base makes it possible to identify it under the accession number NM_014873.
- the sequence of this mRNA has a coding sequence from nucleotide 228 to nucleotide 1340.
- a protein GS-P15 has therefore been identified, resulting from the translation of this mRNA.
- This protein is composed of 370 aa, identified under the number SEQ ID No 67 in the attached sequence list, called angioacyline.
- -GS-N16 an mRNA of 3139 bp identified under the sequence number SEQ ID No: 17 in the sequence list in the appendix.
- a BLAST search makes it possible to identify it under the accession number XM_011833 (Homo sapiens phosducin-like (PDCL) in the GENBANK sequence base.
- sequence of this mRNA has a coding region from nucleotide 167 to nucleotide 1072.
- a GS-P16 protein resulting from the translation of this mRNA has therefore been identified.
- the G proteins play a major role in the transmembrane signaling pathways by transmission of extracellular signals through transmembrane receptors to their appropriate intracellular effectors (Gilman, 1987, Annu. Rev. Biochem., 56, 615- 649; Simon et al, 1991, Science, 252, 802-808).
- the receptor After binding of the ligand, the receptor catalyzes the exchange of GDP for a GTP on the alpha subunit of the heterotrimeric G protein which causes its activation and the dissociation of the alpha- GTP subunit from the beta and gamma subunits (Gilman, 1987 , Annu. Rev. Biochem., .56, 615-649).
- PhLP phosducin-like protein
- - GS-N17 a 2326bp mRNA identified under the sequence number SEQ ID No 18 in the attached sequence list.
- a BLAST search makes it possible to identify it under accession number BC011860 (Ribosomal Protein L3 (RPL3)), in the GENBANK sequence base.
- the protein " RNF20 is still little known, but it is characterized by the presence of the RING FINGER domain.
- the ring finger proteins are likely to play a role in the formation and architecture of large protein complexes which contribute to various cellular processes such as signal transduction, oncogenesis, apoptosis, development, differentiation, gene regulation, ubiquination (Saurin et al, 1996, Trends Biochem. Sci. 21, 208-214; Borden, 2000, J Mol. Biol., 295, 1103-1112; Topcu et al, 1999, Oncogene 18, 7091-7100).
- - GS-N19 a 2167 bp mRNA identified under the number SEQ ID No 20 in the attached sequence list.
- a BLAST search makes it possible to identify it under accession number BC002781 (Protein analogous to splicing factor, arginine / serine-rich 4), in the GENBANK sequence base. The sequence of this mRNA has a coding region, from nucleotide 107 to nucleotide 1591.
- a GS-P19 protein resulting from the translation of this mRNA, presented under the number SEQ ID No. 71 in the annexed sequence list has therefore been identified.
- This protein composed of 494aa is homologous to the splicing factor, arginine / serine-rich 4 (SFRS4) also called SR ⁇ 75 and has the same characteristic domains.
- the coordinated action of the RRM domains determines their specificity for binding to RNAs, while the RS domains function as splicing activators (Câceres et al., 1997, J. Cell Biol., 138, 225-238; Chandler et al ., 1997, Proc. Natl Acad. Sci. USA, 94, 3596-3601; Mayeda et al., 1999, Mol. Cell. Biol., 19, 1853-1863; Graveley and Maniatis, 1998, Mol. Cell, 1 , 765-771).
- Various studies have made it possible to suggest unique functions in the alternative splicing of pre-mRNAs for particular SR proteins, especially since they are differentially expressed in a variety of tissues.
- SR proteins are thus presented as crucial in the regulation of splicing during development and cell differentiation (Zahler et al, Science 1993 Apr 9; 260 (5105): 219-222; Fu, 1993, Nature, 365 (6441): 82-8; sinceceres and Krainer, 1997, (ed. Krainer), Oxford University Press, Oxford, UK, pp. 174-212; Valcarcel and Green, 1996, Trends Biochem Sci, 21 (8): 296-301).
- a recent study shows a variable level of expression of SRp75 in different lymphoid cell lines (Dam et al, 1999, Biochi Biophys Acta; 1446 (3): 317-33.
- - GS-N20 a 5801 bp mRNA identified under the number SEQ ID No 21 in the sequence list in the appendix.
- a BLAST search makes it possible to identify it under the accession number U65090 (Carboxypeptidase D) in the GENBANK sequence base
- - GS-N21 an 8171 bp mRNA identified under the number SEQ ID No 22 in the annexed sequence list.
- a BLAST search makes it possible to identify it under the number NM_004652 (ubiquitin specific Protease 9) in the GENBANK sequence base
- sequence " of this mRNA has a coding sequence from nucleotide 60 to nucleotide 7751.
- a protein resulting from the translation of this mRNA has thus been identified.
- This protein called GS-P21, specific ubiquitin protease 9, is composed of 2563 aa It is identified under the number SEQ ID No 73 in the attached sequence list
- the protein USP9X belongs to the family of UBPs (Ubiquitin proteases), a group of enzymes whose function is to reverse the ubiquitination reaction by removing the ubiquitin residue from many substrates involved in cell division, growth, differentiation, signaling or activation of transcription (Liu et al, 1999, Mol Cell Biol, 4, 3029-38; Zhu et al, 1996, Proc. Natl. Acad. Sci. USA 93: 3275-3279; Verma et al , 1995, Genes Dev.
- UBPs Ubiquitin proteases
- - GS-N22 a 3851 bp mRNA identified under the number SEQ ID No 23 in the annexed sequence list.
- a BLAST search makes it possible to identify it under the accession number NM_002525 (Nardilysine (N-arginine dibasic convertase) (NRDl)) in the GENBANK sequence base.
- This mRNA has a coding sequence from nucleotide 136 to nucleotide 3795.
- a protein GS-P22 resulting from the translation of this mRNA has thus been identified.
- This Nardilysine protein is composed of 1219aa. It is identified under the number SEQ ID No 74 in the sequence list in the appendix.
- N-arginine dibasic convertase (NRD convertase; nardilysine; EC 3.4.24.61) is a metalloendopeptidase of the insulinase family which specifically cleaves peptides (particularly neuroendocrine peptides such as somatosatin-28, dynorphin-A, atrial factor natriuretique) on the N-terminal side of an Arginine residue at the dibasic sites in vitro (Cohen et al, 1995, Methods Enzymol., 248, 703-716; Hospital et al, 1997, Biochem. J., 327, 773 - 779).
- NRD convertase activity is mainly present in tissues endocrines and mainly in the testes (Chesneau, et al, 1994, J. Biol. Chem., 269, 2056-2061). It can be localized both in the cytoplasm and on the cell surface (Hospital et al, 2000, Biochem. J., 349, 587-597).
- NRD convertase In the adult rat, the regulated expression of NRD convertase during spermatogenesis and its concentration in the flagellum suggests a role of this enzyme in the differentiation of male germ cells (Chesneau, et al, 1996, J. Cell Sci. 109, 2737-2745). This enzyme is also proposed to play a specific role in neuronal development (Fumagalli et al, 1998, Genomics 47, 238—245). Recently, NRD convertase has been described as a new specific heparin-binding EGF-like growth factor receptor (HB-EGF) that controls cell migration (Nishi et al, 2001, EMBO J, 20 (13): 3342- 50).
- HB-EGF EGF-like growth factor receptor
- - GS-N23 a 13107 bp mRNA identified under the number SEQ ID No 24 in the attached sequence list.
- a BLAST search makes it possible to identify it under the accession number XM_016303 (myeloid mRNA / lymphoid or mixed-lineage leukemia (MLL)) in the GENBANK sequence base.
- the mRNA sequence identified by the number SEQ ID No 24 has a coding sequence from nucleotide 1872 to nucleotide 10001.
- a protein GS-P23 resulting from the translation of this mRNA has thus been identified. This protein called MLL is made up of 2709aa. It is identified under the number SEQ ID No 75 in the attached sequence list.
- - GS-N47 an mRNA of 14255 bp identified under the number SEQ ID No 48 in the sequence list in the appendix.
- a BLAST search makes it possible to identify it under the accession number L04731 in the GENBANK sequence base.
- This mRNA sequence has no coding sequence. It comprises the sequence GS-N23, with 90% homology.
- - GS-N48 a 11910 bp mRNA identified under the number SEQ ID No 49 in the sequence list in the appendix.
- a BLAST search makes it possible to identify it under the accession number NM_005933 in the GENBANK sequence base.
- the mRNA sequence identified by the number SEQ ID No 48 has a coding sequence from nucleotide 1 to nucleotide 11910.
- a protein GS-P48 resulting from the translation of this mRNA has thus been identified.
- This protein called MLL is made up of 3969aa. It is identified under the number SEQ ID No 99 in the attached sequence list.
- ALL acute lymphoblastic leukemia-1
- MML Myeloid-lymphoid or Mixed-lineage Leukemia
- HRX human tri-thorax
- the proteins structurally derived variants of the altered gene are thought to cause malignant transformation of hematopoietic progenitor cells (Nilson, Br J Haematol, 1996, 93 (4): 966-72; Kobayashi et al, 1995, Leuk Lymphoma, 17 (5-6): 391-9).
- - GS-N24 an mRNA of 10330 identified under the number SEQ ID No 25 in the attached sequence list.
- a BLAST search makes it possible to identify it under the accession number U72937 (Helicase and ATPase dependent on DNA (ATRX), product 2 of alternative splicing) in the GENBANK sequence base.
- - GS-N49 an mRNA of 10452 bp identified under the number SEQ ID No 50 in the sequence list in the appendix.
- a BLAST search makes it possible to identify it under accession number U72936 in the GENBANK sequence base.
- the mRNA sequence identified by the number SEQ ID No 50 has a coding sequence from nucleotide 950 to nucleotide 7816.
- a protein GS-P49 resulting from the translation of this mRNA has thus been identified.
- This protein called ATRX product 1 is composed of 2288aa. It is identified under the number SEQ ID No 100 in the attached sequence list.
- the proteins identified by the numbers SEQ ID No 76 and 100 are 90% homologous.
- This mRNA has a coding sequence from nucleotide 28 to nucleotide 1041.
- a protein GS-P25 resulting from the translation of this mRNA has thus been identified.
- This protein called Sialic Acid-CMP Transporter is composed of 337a. It is identified under the number SEQ ID No 77 in the sequence list in the appendix.
- - GS-N50 an 1874 bp mRNA identified under the number SEQ ID No 225 in the attached sequence list.
- a BLAST search makes it possible to identify it under accession number BC008372 in the GENBANK sequence base.
- the mRNA sequence identified by the number SEQ ID No 225 has no coding sequence.
- the CMP-sialic acid transporter is involved in the maturation process of glycosylation and more particularly sialylation; it allows the translocation of cytosolic CMP-sialic acid across the membrane of the Golgi apparatus necessary for the sialylation of membrane or secreted proteins as well as the lipids in this compartment.
- the regulation of CMP-sialic acid transport is still poorly understood except that an increase in sialylation has been observed on the surface of tumor cells (Santer et al, 03/074073
- - GS-N26 a mRNA of 3982 bp identified under the number SEQ ID No 27 in the sequence list in the appendix.
- a BLAST search makes it possible to identify it under the accession number U26710 in the GENBANK sequence base.
- the sequence of this mRNA has a coding sequence from nucleotide 323 to nucleotide 3271.
- a protein GS-P26 resulting from the translation of this mRNA has thus been identified.
- This protein called cbl-b is made up of 982aa.
- Cbl-b belongs to the Cbl family, highly conserved throughout the species.
- the Cbl proteins are characterized in their N-terminal part by a putative domain binding phosphotyrosines and a RING finger motif in the C-terminal part, the mammalian Cbl proteins contain a proline-rich region, conserved tyrosine residues and a motif. leucine Zipper.
- the Cbl proteins participate in the signaling of proteins of tyrosine kinase receptors, as well as antigens and cytokine receptors by associating with their cytoplasmic tail ensuring signal continuity of these receptors.
- the Cbl protein is recruited by the tyrosine kinase module of these receptors and the phosphorylated tyrosines after cell activation.
- Cbl functions as a stowage protein and associates with molecules containing the SH2 and SH3 domains, including the family of Crk and Vav adapters.
- the Cbl proteins are proposed both as negative regulators of receptor tyrosine kinase signaling (Smit et al, Crit Rev Oncog 1997; 8: 359-79) and as positive modulators of receptor signaling such as the receptor superfamily. TNF (Arron et al, J Biol Chem 2001 Aug 10; 276: 30011-7).
- the Cbl-b protein is involved in setting the activation threshold lymphocytes (Bachmaier et al, Nature 2000, 403: 211-6; Fang et al, J Biol Chem 2001; 276: 4872-8).
- the P85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) has been identified as its substrate.
- Cbl-b by its ligase activity of the protein ubiquitin E3 negatively regulates this regulatory subunit P85 (Fang D, Nat Immunol 2001 Sep; 2 (9): 870-5).
- Cbl-b is also a negative regulator of the signaling of the epidermal growth factor receptor, EGFR (Ettenberg et al, Oncogene 1999; 18: 1855-66; Ettenberg et al, J Biol Chem 2001; 276: 27677-84).
- - GS-N27 a 3385 bp mRNA identified under the number SEQ ID No 28 in the annexed sequence list.
- a BLAST search makes it possible to identify it under the accession number XM_39529 in the GENBANK sequence base. This sequence has 86% homology with the following sequence:
- the mRNA sequence identified under the number SEQ ID No. 27 has a coding sequence from nucleotide 107 to nucleotide 451.
- a protein GS-P27 resulting from the translation of this mRNA has thus been identified.
- This protein called Histone H2A.F / Z variant (H2AV) is composed of 114aa. It is identified under the number SEQ ID No 79 in the attached sequence list.
- Heterogeneity in the structure of nucleosomes can be a mechanism of transcriptional regulation. This heterogeneity is created either by post-translational modifications of histones such as acetylation, phosphorylation, methylation, ubiquitination (Mizzen et al, Cold Spring Harb Symp Quant Biol 1998; 63: 469-81; Workman and guitarist,
- Histone H2A.F / Z is a family of variants of histone H2A which is highly conserved across species and substantially divergent from histone H2A of phase S in given species (Jackson et al, 1996, Trends Biochem. Sci., 221, 466-467; Jiang et al, 1998, Biochem. Biophys. Res. Commun., 245, 613-617).
- H2A.F / Z The exact function of H2A.F / Z is not yet known, but this histone may play a role in transcriptional regulation because in Tetrahymena, its expression is associated with the macronucleus active transcriptionally and in Drosophi its incorporation in chromatin during the development coincides with the start of the expression of the zygotic gene (Clarkson et al, 1999, DNA Cell Biol., 18, 457-462; Stargell et al, 1993, Genes Dev., 7, 2641-2651).
- - GS-N28 an 1128 bp mRNA identified under the number SEQ ID No 29 in the annexed sequence list.
- a BLAST search makes it possible to identify it under the accession number NM_001320 in the GENBANK sequence base.
- This sequence has 77% homology with the sequence identified under the accession number M30448 in the GENBANK database and identified under the number SEQ ID No. 289 in the annexed sequence list.
- This mRNA has a coding sequence from nucleotide 97 to nucleotide 744.
- a protein GS-P28 resulting from the translation of this mRNA has thus been identified.
- This protein called Casein kinase II, Beta unit is composed of 215 aa. She is identified under SEQ ID No 80 in the attached sequence list.
- Casein kinase II (CKII) is a ubiquitous serine / threonine kinase which is localized both in the cytosol and in the nucleus of eukaryotic cells. CKII phosphorylates over a hundred substrates, many of which are involved in cell division control and signal transduction (review: Allende and Allende, 1995, The FASEB Journal, Vol 9, 313-323). CKII exists in the form of a tetramer composed of two alpha and / or alpha 'catalytic subunits and two regulatory (beta) subunits.
- the beta subunit seems to act to stabilize the alpha and / or alpha 'subunits and also influence the specificity of the substrate and the kinetics properties of the enzyme (Dobrowolska et al, 1999, Mol Cell Biochem, 191 (1-2) : 3-12).
- hormones or growth factors such as insulin, IGF-I, EGF (Sommercorn et al, 1987, Proc. Natl Acad Sci USA, 84, 8834-8838; Klarlund et al,
- - GS-N29 an 18207 bp mRNA identified under the number SEQ ID No 30 in the attached sequence list.
- a BLAST search makes it possible to identify it under the accession number AF156100 in the GENBANK sequence base.
- the sequence of this mRNA has a coding sequence from nucleotide 230 to nucleotide 17140.
- a protein GS-P29 resulting from the translation of this mRNA has thus been identified.
- This protein called Hemicentine is made up of 5636aa. It is identified under the number SEQ ID No 81 in the attached sequence list.
- This GS-29 sequence includes the GS-N52 sequence below, showing 99% homology to it.
- GS-N52 an 8546 bp mRNA identified under the number SEQ ID No 52 in the attached sequence list.
- a BLAST search makes it possible to identify it under accession number AJ306906 in the GENBANK sequence base.
- sequence of this mRNA has a coding sequence for a GS-P52 protein of 2673aa identified under the number SEQ ID No 101 in the sequence list in the appendix.
- hemicentine is a protein from the extracellular matrix of the immunoglobulin superfamily, which is involved in attachment and cell migration on the basement membrane (Vogel and Hedgecock, 2001, Development, 128 (6): 883- 94). Its role in the regulation of angiogenesis is not described above current.
- This protein contains the fibulin-6 sequence which belongs to the family of fibulins, proteins of the extracellular matrix and of the blood of which the two most studied members are fibulin 1 and fibulin 2 (Alexande and Detwiler, 1984, Biochem. J., 217.67-71; Argraves, et al, 1990, J. Cell Biol., 111.3155-3164; Kluge et al, 1990, Eur. J.
- proteins involved in cell adhesion such as fibronectin, laminin, fibrinogen (Brown et al, 1994, J Cell Sci, 107 (Pt 1), 329-38; Tran et al, 1995, J Biol Chem , 270 (33)
- Fibulin 1 has been described that may play a role in regulating the neurotrophic activity of the amyloid beta precursor protein (Ohsawa et al, 2001, J Neurochem; 76 (5): 1411-20), in the homeostasis and thrombosis (Tran et al, 1995, J Biol Chem, 270 (33): 19458-64).
- fibulin 6 is not yet known, and in particular, no role of this protein has been described until today in the regulation of angiogenesis.
- - GS-N30 a 4325 bp mRNA identified under the number SEQ ID No 31 in the attached sequence list.
- a BLAST search makes it possible to identify it under the accession number NM_015180 in the GENBANK sequence base.
- sequence of this mRNA has a coding sequence from nucleotide 123 to nucleotide 3041. It has thus been identified a GS-P30 protein resulting from the translation of this mRNA.
- This protein called SYNE-2 is composed of 1092aa and is identified under the number SEQ ID No 82 in the sequence list in the appendix.
- - GS-N31 a 4248 bp mRNA identified under the number SEQ ID No 32 in the attached sequence list.
- a BLAST search makes it possible to identify it under accession number AF261758 in the GENBANK sequence base.
- the sequence of this mRNA has a coding sequence from nucleotide 100 to nucleotide 1650.
- a protein GS-P31 resulting from the translation of this mRNA has thus been identified.
- This protein called Seladine-1 is made up of 516aa. It is identified under the number SEQ ID No 83 in the attached sequence list.
- This mRNA sequence identified under the number SEQ ID No 32 in the sequence list in the appendix is homologous with a sequence of 4187 bp.
- a BLAST search makes it possible to identify it under accession number D13643 in the GENBANK sequence base. It is identified under the number SEQ ID No 53 in the attached sequence list.
- - GS-N32 an mRNA of 7764 bp identified under the number SEQ ID No 33 in the sequence list in the appendix.
- a BLAST search makes it possible to identify it under the accession number NM_001271 in the GENBANK sequence base.
- the sequence of this mRNA has a coding sequence from nucleotide 708 to nucleotide 5927. It has thus been identified a GS-P32 protein resulting from the translation of this mRNA. This protein called CHD2 is made up of 1739aa. It is identified under the number SEQ ID No 84 in the attached sequence list.
- the CHD2 protein belongs to the family of CHD proteins characterized by a chromodomain.
- the "chromo" (CHRromatin Organization Modifier) domain is a conserved region of approximately 60 amino acids found in a variety of proteins including the HP1 proteins of Drosophila melanogaster, which binds to heterochromatin; 4 genes of this family have been identified in the human genome: CHD1, CHD2, CHD3 and CHD4 (Woodage et al., 1997, 94, 11472-11477).
- the chromodomain gives the protein a role in the chromatin compaction (Paro, 1990, Trends Genêt. 6: 416-421; Singh et al, 1991, Nucleic Acids Res.
- CHD contains a second conserved domain, the Myb domain which is involved in DNA binding (Klempnauer and Sippel, 1987, EMBO J., 6: 2719-2725).
- CHD2 contains the SNF2 domain, found in proteins involved in a variety of processes such as regulating transcription (e.g.
- CHDs can play an important role in regulating gene transcription. (Delmas et al, 1993, Proc. Natl. Acad. Sci., 90, 2414-2418; oodage et al, 1997, Proc. Natl. Acad. Sci. USA, 94, 11472-11477; Tran et al, 2000, The EMBO Journal, 19.2323-2331)
- the BRD2 protein is characterized by two bromodomains as is the case with the transcription factor BDFl (Tamkun, 1995, Curr. Opin. Genêt. Dev, 5: 473-477) or the protein TAFII250, the largest subunit of the multiprotein complex, TFIID involved in the initiation of transcription (Jacobson et al, 2000, Science, 288 (5470): 1422-5).
- BDFl transcription factor
- TAFII250 the largest subunit of the multiprotein complex
- TFIID the largest subunit of the multiprotein complex
- the exact function of this domain is not yet known but it is thought to be involved in protein-protein interactions and may be important for the assembly or activity of the multiple component complexes involved in chromatin modification and control transcription of a wide variety of eukaryotic genes including those that control growth.
- - GS-N34 a 2983 bp mRNA identified under the number SEQ ID No 35 in the attached sequence list.
- a BLAST search makes it possible to identify it under accession number BC007429 in the GENBANK sequence base.
- the sequence of this mRNA has a coding sequence from nucleotide 200 to nucleotide 1069.
- a protein GS-P34 resulting from the translation of this mRNA has thus been identified.
- This protein called Syntaxine 3A is composed of 289aa. It is identified under the number SEQ ID No 86 in the attached sequence list.
- Syntaxin 3A belongs to the syntaxin / epimorphin family which is characterized by a size between 30 and 40 kDa, a highly hydrophobic C-terminal end which is probably involved in the anchoring of the protein in the membrane and a central region well preserved which appears to be in a "coiled-coil" conformation. The specific profile of this family is based on the most conserved region of the "coiled-coil” domain. Syntaxins are involved in the intracellular transport of vesicles and their attachment to the plasma membrane. Recent work suggests that different syntaxin isoforms can interact with a defined group of membrane transport proteins and thus regulate their " transport activity (review: Saxena et al, 2000, Curr Opin Nephrol Hypertens, 9 (5): 523-7).
- Syntaxin 3A is one of the two isoforms (3A and 3B) identified in humans, resulting from an alternative splicing of the same gene.
- the increase in the expression of syntaxin 3A has already been demonstrated during various biological processes such as the neutrophil differentiation of HL-60 cells or in the dentate granule cells during propagation. synaptic plasticity in the nervous system (Rodger et al, 1998, J Neurochem, 71 (2): 666-675; Martin-Martin et al, 1999, J Leukoc Biol, 65 (3): 397-406).
- - GS-N35 an mRNA of 12227bp identified under the number SEQ ID No 36 in the sequence list in the appendix.
- a BLAST search makes it possible to identify it under the accession number NM_015001 in the GENBANK sequence base.
- the sequence of this mRNA has a coding sequence from nucleotide 205 to nucleotide 11199.
- a protein GS-P35 resulting from the translation of this mRNA has thus been identified.
- This protein called SHARP is made up of 3664aa. It is identified under the number SEQ ID No 87 in the sequence list in the appendix.
- SHARP SMART / HDAC1 Associated Repressor Protein
- RD repression domain
- NuRD nucleosome remodeling and histone deacetylase activities
- HDAC1 and HDAC2 histone deacetylases
- SHARP binds to the ARS coactivator of the steroid receptor RNA through an intrinsic RNA-binding domain and suppresses the transcription activity of the steroid receptor. In this way, SHARP has the ability to modulate both ligated and unligued nuclear receptors.
- HDAC Histone deacetylases
- the protein pRb tumor suppressor called retinoblastoma acts to control cell proliferation, inhibit apoptosis and induce cell differentiation by associating with a large number of proteins (review: Morris and Dyson, 2001, Adv Cancer Res; 82: 1-54).
- Protein HIP1 is composed of 914aa. It is identified under the number SEQ ID No 89 in the sequence list in the appendix.
- the protein HIPl (“Huntingtin interacting protein 1”) is a 116 kDa protein which binds the protein
- TM4SF2 The sequence of this mRNA has a coding sequence from nucleotide 81 to nucleotide 815.
- a protein GS-P44 resulting from the translation of this mRNA has thus been identified.
- This protein called TM4SF2 is made up of 244aa. It is identified under the number SEQ ID No 96 in the sequence list in the appendix.
- - GS-N45 A 2081 bp mRNA identified under the number SEQ ID No 46 in the attached sequence list.
- a BLAST search makes it possible to identify it under the accession number HSA133133 in the GENBANK sequence base.
- Ecto-ATPases are ubiquitous enzymes in cells which hydrolyze extracellular ATP and ADP to AMP (review: Plesner, 1995, Int Rev Cytol, 158: 141-214).
- the presence of ATPDases has been demonstrated on aortic endothelial cells and smooth muscle cells and described as being able to play a regulatory role in homeostasis and platelet reactivity by hydrolyzing ATP and ADP (Robson et al, 1997, J Exp Med, 185 (1): 153-63).
- Vascular ATPDase is closely homologous to the CD39 glycoprotein, the accession number in the GENBANK base is S73813 and is identified under the number SEQ ID No.
- an oligonucleotide specific for each of the identified genes chosen from the oligonucleotides identified by the sequences SEQ ID No.: 103 to SEQ ID. : 148 in the annexed sequence list was introduced into the expression vector pCI-neo Vector in the antisense orientation.
- GS-V1 to GS-V46 identified by their sequence SEQ ID No: 149 to SEQ ID No: 194 in the sequence list in the appendix were used to repress the expression of the gene coding for this mRNA in cells human endothelial cells following their transfection with this vector.
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EP20090000624 EP2161280A3 (fr) | 2002-03-04 | 2003-03-04 | Gènes impliqués dans la régulation de l'angiogènese, préparations pharmaceutiques les contenant et leurs applications |
EP05290552A EP1566387A3 (fr) | 2002-03-04 | 2003-03-04 | Gènes impliqués dans la régulation de l'angiogenese, préparations pharmaceutiques les contenant et leurs applications |
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FR0204546 | 2002-04-11 | ||
FR0204546A FR2836687A1 (fr) | 2002-03-04 | 2002-04-11 | Genes impliques dans la regulation de l'angiogenese, preparations pharmaceutiques les contenant et leurs applications |
PCT/FR2003/000695 WO2003074073A2 (fr) | 2002-03-04 | 2003-03-04 | Genes impliques dans la regulation de l'angiogenese, preparations pharmaceutiques les contenant et leurs applications. |
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AU2002310256A1 (en) * | 2001-06-05 | 2002-12-16 | Exelixis Inc. | Ppp2cs as modifiers of the p53 pathway and methods of use |
US7803906B2 (en) | 2002-03-22 | 2010-09-28 | Gene Signal International Sa | Composition comprising an angiogenesis related protein |
FR2837391B1 (fr) * | 2002-03-22 | 2007-04-20 | Gene Signal | Genes regulateurs de l'angiogenese, preparations pharmaceutiques les contenant et leurs applications |
WO2005014819A1 (fr) * | 2003-08-11 | 2005-02-17 | Kumamoto Technology & Industry Foundation | Antigene du cancer de l'oesophage et utilisation de celui-ci |
EP1591534A1 (fr) * | 2004-04-01 | 2005-11-02 | Stichting Sanquin Bloedvoorziening | Une méthode de genotyping des antigènes de cellules de sang et un kit approprié aux genotyping des antigènes de cellules de sang |
FR2880631A1 (fr) * | 2005-01-10 | 2006-07-14 | Gene Signal | Genes impliques dans la regularisation de l'angiogenese, preparations pharmaceutiques les contenant et leurs applications |
JPWO2007069423A1 (ja) * | 2005-12-12 | 2009-05-21 | 独立行政法人理化学研究所 | アレルギー診断用マーカー |
US20080194478A1 (en) * | 2007-02-09 | 2008-08-14 | Gene Signal International Sa | Wound healing agent and composition |
EP2371377A1 (fr) * | 2007-02-09 | 2011-10-05 | Gene Signal International SA | Agent et composition de cicatrisation |
EP1955704A1 (fr) * | 2007-02-09 | 2008-08-13 | Gene Signal International Sa | Agent et composition de cicatrisation |
DE602007009797D1 (de) * | 2007-04-11 | 2010-11-25 | Gene Signal Int Sa | Antitumorheilmittel, Medikament, Zusammensetzung und Verwendung davon |
CA2683463A1 (fr) * | 2007-04-11 | 2008-10-23 | Gene Signal International Sa | Drogue, medicament, composition anti-tumoraux, et leurs utilisation |
US8372810B2 (en) | 2007-04-11 | 2013-02-12 | Gene Signal International Sa | Anti-tumor drug, medicament, composition, and use thereof |
ES2674710T3 (es) | 2007-05-16 | 2018-07-03 | Gene Signal International Sa | Fármaco, medicamento, composición antitumoral y uso de los mismos |
US8288334B2 (en) * | 2010-06-14 | 2012-10-16 | Gene Signal International Sa | Peptides for wound healing |
WO2012135500A1 (fr) | 2011-03-29 | 2012-10-04 | The General Hospital Corporation | Protéines pliées de type thioredoxine manipulées |
US9682144B2 (en) | 2011-06-30 | 2017-06-20 | Gene Signal International, Sa | Composition comprising inhibitors of IRS-1 and of VEGF |
CN102558311B (zh) * | 2012-02-13 | 2014-02-19 | 中山大学 | 一种慢性乙型病毒性肝炎相关基因tmem2的突变蛋白、编码基因及其应用 |
US20150005183A1 (en) * | 2013-07-01 | 2015-01-01 | Expression Pathology, Inc. | Protein biomarkers of late stage breast cancer |
US10385096B2 (en) * | 2016-08-30 | 2019-08-20 | Council Of Scientific & Industrial Research | Pro-Amb reverse turn restricted bioactive peptide analogues |
US11959083B2 (en) * | 2016-10-07 | 2024-04-16 | Secarna Pharmaceuticals Gmbh & Co. Kg | Immunosuppression-reverting oligonucleotides inhibiting the expression of CD39 |
WO2021150840A1 (fr) * | 2020-01-23 | 2021-07-29 | University Of Southern California | Antagonisme en tant que thérapie pour des protéinopathies tdp-43 |
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US5641756A (en) * | 1993-07-27 | 1997-06-24 | Hybridon, Inc. | Modified VEGF oligonucleotides |
US5534913A (en) | 1994-03-31 | 1996-07-09 | At&T Corp. | Apparatus and method for integrating downstream data transfer over a cable television channel with upstream data carrier by other media |
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FR2798674B1 (fr) * | 1999-09-21 | 2004-01-30 | Mahmood Salman Al | Procede d'identification de nouveaux genes impliques dans la regulation de l'angiogenese, etude de ces genes et leur utilisation a des fins therapeutiques |
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AU2003233359A8 (en) | 2003-09-16 |
EP1566387A2 (fr) | 2005-08-24 |
WO2003074073A3 (fr) | 2005-01-13 |
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US20090264364A1 (en) | 2009-10-22 |
JP4621762B2 (ja) | 2011-01-26 |
EP2161280A3 (fr) | 2012-07-18 |
WO2003074073A2 (fr) | 2003-09-12 |
US7553492B2 (en) | 2009-06-30 |
AU2003233359A1 (en) | 2003-09-16 |
CA2477662A1 (fr) | 2003-09-12 |
US20050153917A1 (en) | 2005-07-14 |
JP2005532788A (ja) | 2005-11-04 |
EP2161280A2 (fr) | 2010-03-10 |
JP2009050262A (ja) | 2009-03-12 |
FR2836687A1 (fr) | 2003-09-05 |
US8133877B2 (en) | 2012-03-13 |
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