EP1105483A1 - Gene, die eine rolle spielen in der molekularen mechanismen der tumorbekämpfung und/oder virusresistenz - Google Patents

Gene, die eine rolle spielen in der molekularen mechanismen der tumorbekämpfung und/oder virusresistenz

Info

Publication number
EP1105483A1
EP1105483A1 EP99965353A EP99965353A EP1105483A1 EP 1105483 A1 EP1105483 A1 EP 1105483A1 EP 99965353 A EP99965353 A EP 99965353A EP 99965353 A EP99965353 A EP 99965353A EP 1105483 A1 EP1105483 A1 EP 1105483A1
Authority
EP
European Patent Office
Prior art keywords
sequence
gene
medicament
vector
expression
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Withdrawn
Application number
EP99965353A
Other languages
English (en)
French (fr)
Inventor
Robert Amson
Adam Telerman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Molecular Engines Laboratories
Original Assignee
Molecular Engines Laboratories
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Molecular Engines Laboratories filed Critical Molecular Engines Laboratories
Publication of EP1105483A1 publication Critical patent/EP1105483A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4747—Apoptosis related proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/022—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from an adenovirus
    • 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
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/023—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a poxvirus
    • 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
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/027—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a retrovirus
    • 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
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/028—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a herpesvirus

Definitions

  • the present invention relates to the detection of genes involved in the molecular pathways of tumor suppression and / or resistance to viruses.
  • the present invention was made possible by the isolation of cDNA corresponding to messenger RNAs expressed or repressed during tumor suppression and / or during the process of apoptosis induced by the p53 suppressor gene.
  • mice nullizygous for p53 were much more sensitive to the formation of tumors. It has also been demonstrated that, in cancers, the p53 gene is very often altered and leads to the production of proteins incapable of conveying the message of apoptosis. It is this feature which has been implemented in the context of the present invention.
  • the present invention is based on the observation that it is not possible, or at least that it seems very difficult, to set up a direct substitution therapy during a dysfunction of the p53 gene. Indeed, the mutated p53 as it is in cancer will cancel the physiological effect of normal p53. It was therefore necessary to give up, at least initially, a substitution therapy acting directly at the level of p53.
  • the present invention has therefore endeavored to study the genes located upstream and downstream of p53 in order to “bypass” the difficulty mentioned above.
  • a global raking of gene expression was carried out in a malignant line (K562) and a derived cell (KS) with a suppression of the phenotype.
  • malignant more particularly in a cell expressing normal p53 (KS) in its function and in a cell not expressing p53 (K562).
  • the comparison of the expressed genes made it possible to highlight genes expressed differently, that is to say expressed in one of the cells whereas they are not it in the other (genes can be turned on or off).
  • sequences are sequences whose function is known and which are involved in the process of suppressing the malignant phenotype and / or of apoptosis induced by the suppressor gene p53 and / or in the resistance to viruses.
  • the present invention relates to new sequences and the genes comprising them as well as the use of these sequences, both at the diagnostic level and at the therapy level, as well as for the production of models intended for testing anti products. -cancerous and anti-viral.
  • the present invention firstly relates to a nucleotide sequence corresponding to a gene comprising:
  • sequences 1 to 15 constitute only part of the genes in question, but that the present invention covers both the nucleotide sequence corresponding to the entire gene as fragments of this gene, in particular when they code for an equivalent protein as will be described below.
  • the nucleotide sequences can be either DNA or RNA OR sequences in which some of the nucleotides are unnatural, either to improve their pharmacological properties or to allow their identification.
  • sequences mentioned in (b) are essentially the total or partial complementary sequences (in particular for the cases mentioned above).
  • the invention also relates to the nucleotide sequences of the genes having a strong homology with the genes mentioned above, preferably a homology greater than 80% on the essential parts of said genes, ie in general at least 50% of the sequence, preferably the homology on these parts will be greater than 90%.
  • the present invention also relates to the sequences coding for the same protein, taking into account the degeneration of the genetic code, but also for equivalent proteins, that is to say producing the same effects. , in particular proteins deleted and / or having undergone point mutations.
  • sequences according to the present invention are more particularly the sequences which are induced or inhibited during cellular apoptosis, in particular those induced by p53 and / or p21 and / or TSAP3 (HUMSIAH) and / or antisense-TSIP2 (antisens-PSl) .
  • these sequences correspond to genes whose cellular expression is activated by at least one of the transfectants chosen from the group comprising the p21 transfectants, the TSAP3 transfectants and the TSIP2 antisense transfectants.
  • Said genes are grouped in TSAP or "Tumor Suppressor Activated Pathway ", and named TSAP 9 to TSAP 22 corresponding to IND.SEQ 1 to 14, and TSIP or" Tumor Suppressor Inhibited Pathvay ", and called TSIP 3, corresponding to IND.SEQ 15.
  • nucleotide sequences corresponding to the TSAP genes are sequences expressed during the apoptosis process while when they are not expressed the oncogenesis process continues. It is therefore interesting:
  • Replacement therapy may be carried out by gene therapy, that is to say by introducing the TSAP gene with the elements which allow its expression in vivo.
  • gene therapy is to say by introducing the TSAP gene with the elements which allow its expression in vivo.
  • vectors viral or non-viral, for example adenovirus, retrovirus, herpes virus or poxvirus. Most of the time, these vectors are used in defective forms which will serve as vehicles for the expression of TSAP with or without integration.
  • the vectors can also be synthetic, that is to say mimic viral sequences, or else consist of DNA or naked RNA according to the technique developed in particular by the company VICAL. In most cases, it will be necessary to provide targeting elements ensuring expression of specific tissues or organs, in fact, it is not possible to envisage activating an uncontrolled apoptosis phenomenon.
  • the present invention therefore relates to all of the vectors described above.
  • the present invention also relates to cells transformed with an expression vector as described above as well as the protein obtainable by culturing transformed cells.
  • Expression systems for producing proteins can be either eukaryotic systems such as the foregoing vectors or prokaryotic systems in bacteria cells.
  • One of the advantages of the present invention is that it has demonstrated the involvement of several genes in apoptosis; thus, the overexpression of one of the genes by gene therapy may, for some of them, lead to apoptosis only the cells in which other deregulated genes are already expressed, that is to say malignant cells.
  • the present invention also relates, as a medicament, to a compound ensuring the cellular expression of at least one of the preceding nucleotide sequences when it is induced during apoptosis and / or tumor suppression, in particular TSAP 9 genes to TSAP 22, or on the contrary ensuring the inhibition of cellular expression of at least one cell sequence as described above when it is inhibited during apoptosis and / or tumor suppression, in particular TSIP 3. It may for example be an activated nucleotide ensuring the blocking of the nucleotide sequence or else a monoclonal antibody raised against the protein (s) encoded by the nucleotide sequence.
  • nucleotide sequences in sense or antisense strategy that is to say which can block the expression of TSIP or, on the contrary, acting by upstream, promoting the expression of TSAP.
  • the present invention relates in particular to the use of the above drugs as an anti-cancer agent.
  • the product of the TSAP 9 to 22 and TSLP 3 genes is also useful as an antiviral agent, as will appear on reading the example.
  • the present invention therefore also relates to the use of the above drugs as an antiviral agent.
  • the present invention relates, as a diagnostic agent for determining the predisposition to cancer, all or part of the sequences according to the invention to be used as a nucleotide probe or as an amplification primer, but also as a diagnostic agent for determining the predisposition to cancer an antigen corresponding to all or part of the proteins encoded by the sequence according to the invention or the corresponding antibodies, optionally after culture.
  • the diagnostic methods are known, they can be, for example, techniques of microsequencing of the variable parts after isolation and possible amplification, or detection methods of the RFLP type, or simple amplification in particular. Differential techniques can, in particular, make it possible to highlight the difference between normal and abnormal TSAP (or TS P).
  • the invention also relates to models implementing the above sequences.
  • TSAP 9 with a mouse chaperonin containing the TCP-1 gene (9), the inventors have found a strong homology which TSAP 13 has with the p40.5 subunit of the human proteasome
  • Chaperonins are involved in the folding process and the assembly of proteins in the eukaryotic cytosol. They are suspected of slowing down this folding by trapping intermediaries who would otherwise aggregate.
  • actin tubulin
  • the proteasome like the ubiquitin, is the main component of the major proteolytic system responsible for the breakdown of many intracellular proteins, including aberrant proteins resulting from mutations or environmental stress.
  • the p40.5 subunit of the human proteasome 26S has recently been demonstrated, as well as its counterpart in the yeast Nas7p.
  • the mRNA corresponding to the above subunit is more particularly expressed in the pancreas, the placenta, the testes, the heart and the skeletal muscle. It also appears that yeast cells deficient in Nas7p are particularly sensitive to heat stress. This helps to suggest that the function of the 26S proteasome is degraded during heat stress.
  • SNARE proteins Soluble N-ethylmaleimide-sensitiye factor-attachment protein receptor
  • proteins are proteins whose differential expression and associations are involved in the organization of the membrane compartments of cells. These proteins are specifically localized in the region of the Golgi apparatus, endosomes and lysosomes, which suggests that they play a role in regulating membrane exchanges from these organelles. More particularly, syntaxin 11 would be localized in the post-Golgi region.
  • Figure 1 shows the extended TSAP 13 sequence (SEQ ED No. 5).
  • the underlined part corresponds to the sequence as originally updated by the inventors.
  • the bold characters correspond to the sequence showing 100% homology with the p40.5 subunit of the human 26S proteasome.
  • Figure 2 shows the extended TSAP 21 sequence (SEQ ID No. 13).
  • the underlined part corresponds to the sequence as originally updated by the inventors.
  • Bold characters correspond to the sequence showing 100% homology with syntaxin 11 of the SNARE protein group
  • the K562 line is a tumor line, derived from a chronic erythromyeloid type leukemia. It is characterized in particular by a Philadelphia chromosome which contains the translocation (9,22), where there is a rearrangement of the bcr gene with the proto-oncogene abl. This line also has an abnormal karyotype and overexpresses the oncogenes myc and pim-1. These lines are described in reference A. Telerman et al. : A model for tumor suppression using H-1 parvovirus, Proc. Natl. Acad. Sci. USA, Vol. 90, pp. 8702-8706, September 1993. In summary, a K562 monoclone was infected with the parvovirus H-1.
  • the inventors derived from a population of malignant cells U937 the lines US3 and US4 which are resistant to parvovirus H-1 and which exhibit a suppression of the malignant phenotype. These lines are described in reference (7).
  • Ml myeloid leukemia cells and Ml cells were stably transfected with a temperature-sensitive mutant val 135 p53
  • Line U937 transfected with p21 WAF1 the complete coding part of the cDNA of the p21 WAF1 gene was cloned into the vector pBK-RSV (Stratagene, La JoUa, California). 3.5 million U937 cells were transfected with 20 micrograms of DNA / 30 micrograms Lipofectin (Life Technologies).
  • the stable transfectants were selected using 1.5 mg / ml of
  • Line U937 transfected with TSIP2 (PSI) in the antisense position the complete coding part of the cDNA of the TSIP2 gene (PSI) was cloned in the antisense position in the vector pBK-RSV (Stratagene, La Jolla, California). 3 million cells
  • G418 (Sigma). The characteristics of this line, describing in particular a slowdown in growth, activation of apoptosis and suppression of the malignant phenotype, have been described in reference (8).
  • Line U937 transfected with TSAP3 ( ⁇ UMSIAH): the complete coding part of the cDNA of the TSAP3 gene has been cloned into the vector pBK-RSV
  • PolyA + mRNA is still used twice purified on an oligodT column using Fast Track (Invitrogen, San Diego CA). After reverse transcription (M-MLV Reverse Transcriptase, Gibco BRL) on 0.05 ⁇ g of polyA + using 20 ⁇ M of each of the dNTPs (Boehringer-Mannheim), no added dNTPs are added to the final PCR mixture. A “hot start” at 94 ° C for 5 minutes is carried out before the PCR (GeneAmp PCR System 9600 Perkin Elmer Cetus). The samples are quickly cooled on ice water.
  • a touch down (2) of 10 cycles of 50 ° C to 40 ° C is carried out (94 ° C 30 seconds - 50 ° C 1 minute - 72 ° C 30 seconds), followed by 35 cycles (94 ° C 30 seconds - 40 ° C 1 minute - 72 ° C 30 seconds) and a final extension of 5 minutes at 72 ° C.
  • PCR products are separated on 6% non-denaturing polyacrylamide gels (4). The gels are exposed without drying. Each differential presentation is performed by comparing M1S6 and LTR6 at 37 ° C and after 4 hours of incubation of the two cell lines at 32 ° C.
  • differential presentation procedure is repeated in 3 different experiments to confirm perfect reproducibility.
  • the differentially expressed bands are cut from the gel, eluted and re-amplified (1).
  • PCR products are subcloned using the TA-cloning system (Invitrogen, San Diego CA) following the directions provided.
  • RNA extraction analyzes and Northern blots probes
  • Total RNA is extracted with Trizol (Life Technologies).
  • the polyl + RNAs are prepared using the OligotexdT kit (Qjagen, CA). 30 ⁇ g of total RNA or 2 ⁇ g of polyA + RNA are separated on 1% agarose 1 x MOPS / 2% formaldehyde gel, transferred to nylon membrane (Hybond N +, Applig necessarily, France) as described above ( 5).
  • the Northern blots are hybridized with probes labeled with P 32 on the TSAP and TSEP inserts and washed as described previously (5).
  • the Northern blots are hybridized with a cyclin G probe (6).
  • the bots are hybridized with a " GAPDH probe.
  • Different Northern blots (Clontech CA) are used under identical conditions and hybridized for control with a ⁇ -actin probe. The Northern blots are exposed for 10 days to - 80 ° C.
  • Example 1 The aim sought is to characterize the molecular pathways which lead to the suppression of cancer.
  • the KS, KS2 and KS3 cells have a reduction in their tumorigenicity by 90%, while cultivated in "soft agar", these same KS lines have a reduction in their tumorigenicity in vivo when injected into Scid immunosuppressed mice - Scid.
  • this suppression of the malignant phenotype went hand in hand with a re-expression of the suppressor gene p53.
  • TSAP 9 is homologous to chaperonins.
  • Table 1 brings together the characterized molecules, showing the primers as well as the sizes of the mRNAs detected by Northern blot. Of these 15 molecules, all are induced in KS cells, except TSIP 3, the expression of which is inhibited during the suppression of the malignant phenotype.
  • the 15 molecules that we isolated therefore encode genes whose overexpression (TSAP 9 - TSAP 22) or inhibition (TSIP 3) is associated not only with the suppression of cancer but also with resistance to the parvovirus H-1. These genes therefore code for molecules that are part of the molecular pathways for cancer suppression and are potential suppressor genes.
  • U937 are transfected with the TSIP2 gene (PSI) in the antisense position.
  • Table 1 reports the results of differential expressions analyzed by Northern blot of the various probes (TSAP9-
  • TSAP22, TSEP3 of the K562 / KS model as well as of the other U937 / US3-US4 models, that is to say in a tumor suppression model in which the p21 gene is activated by the independent p53 pathway.
  • These cDNAs are therefore activated in two different cellular systems for tumor suppression (the erythroleukemia model K562 / KS and the myelomonocytic model U937 / US).
  • the p21 transfectants or TSAP3 transfectants or antisense-TSIP2 transfectants are capable of activating the molecular machinery for tumor suppression common to the U937 / US and K562 / KS systems.
  • Table 3 summarizes the differential expression characteristics of the cDNA clones by Northern blot.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Toxicology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
EP99965353A 1998-08-05 1999-06-18 Gene, die eine rolle spielen in der molekularen mechanismen der tumorbekämpfung und/oder virusresistenz Withdrawn EP1105483A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9810077A FR2782085B1 (fr) 1998-08-05 1998-08-05 Genes impliques dans les voies moleculaires de la suppression tumorale et/ou la resistance aux virus
FR9810077 1998-08-05
PCT/FR1999/001479 WO2000008147A1 (fr) 1998-08-05 1999-06-18 Genes impliques dans les voies moleculaires de la suppression tumorale et/ou la resistance aux virus

Publications (1)

Publication Number Publication Date
EP1105483A1 true EP1105483A1 (de) 2001-06-13

Family

ID=9529433

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99965353A Withdrawn EP1105483A1 (de) 1998-08-05 1999-06-18 Gene, die eine rolle spielen in der molekularen mechanismen der tumorbekämpfung und/oder virusresistenz

Country Status (6)

Country Link
US (1) US6956110B1 (de)
EP (1) EP1105483A1 (de)
JP (1) JP2002524041A (de)
CA (1) CA2339322A1 (de)
FR (1) FR2782085B1 (de)
WO (1) WO2000008147A1 (de)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2818661A1 (fr) * 2000-12-26 2002-06-28 Molecular Engines Laboratoires Gene implique dans la regulation de l'apoptose
FR2818747B1 (fr) * 2000-12-26 2003-05-16 Molecular Engines Laboratoires Procede de criblage base sur l'interaction siah-numb
FR2820757A1 (fr) * 2001-02-13 2002-08-16 Molecular Engines Lab Sequences impliquees dans les phenomenes de suppression tumorale, reversion tumorale, apoptose et/ou resistance aux virus et leur utilisation comme medicamments
WO2003025176A2 (fr) * 2001-09-17 2003-03-27 Molecular Engines Laboratories Sequences impliquees dans les phenomenes de suppression tumorale, reversion tumorale, apoptose et/ou resistance aux virus et leur utilisation comme medicaments
WO2003025177A2 (fr) * 2001-09-17 2003-03-27 Molecular Engines Laboratories Sequences impliquees dans les phenomenes de suppression tumorale, reversion tumorale, apoptose et/ou resistance aux virus et leur utilisation comme medicaments
WO2003040369A2 (fr) * 2001-09-17 2003-05-15 Molecular Engines Laboratories Sequences impliquees dans les phenomenes de suppression tumorale, reversion tumorale, apoptose et/ou resistance aux virus et leur utilisation comme medicaments
WO2003025175A2 (fr) * 2001-09-17 2003-03-27 Molecular Engines Laboratories Sequences impliquees dans les phenomenes de suppression tumorale, reversion tumorale, apoptose et/ou resistance aux virus et leur utilisation comme medicaments
FR2822475B1 (fr) * 2002-03-20 2005-12-30 Molecular Engines Lab Sequences impliquees dans les phenomenes de suppression tumorale, reversion tumorale, apoptose et/ou resistance aux virus et leur utilisation comme medicaments
WO2003087372A2 (fr) * 2002-04-12 2003-10-23 Molecular Engines Laboratories Facteur de croissance derive d’hepatome et son utilisation
WO2003087153A1 (fr) * 2002-04-12 2003-10-23 Molecular Engines Laboratories Proteine knox-25 en doigt de zinc de type kruppel de souris et son utilisation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10500001A (ja) * 1994-01-31 1998-01-06 キャンサー リサーチ キャンペーン テクノロジー リミティド 折り畳みタンパク質
EP0868512B9 (de) * 1995-12-20 2006-09-06 Cerenis Nukleotidsequenzen, proteine, medikamente und diagnoseagentien zur anwendung in krebsbehandlung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0008147A1 *

Also Published As

Publication number Publication date
CA2339322A1 (fr) 2000-02-17
JP2002524041A (ja) 2002-08-06
FR2782085A1 (fr) 2000-02-11
US6956110B1 (en) 2005-10-18
FR2782085B1 (fr) 2002-12-13
WO2000008147A1 (fr) 2000-02-17

Similar Documents

Publication Publication Date Title
EP0868512B9 (de) Nukleotidsequenzen, proteine, medikamente und diagnoseagentien zur anwendung in krebsbehandlung
EP1105483A1 (de) Gene, die eine rolle spielen in der molekularen mechanismen der tumorbekämpfung und/oder virusresistenz
WO1993023549A2 (fr) Acide nucleique correspondant a un gene du chromosome 22 implique dans les translocations chromosomiques recurrentes associees au developpement de tumeurs cancereuses
FR2710074A1 (fr) Gène GRB3-3, ses variants et leurs utilisations.
EP0877758B1 (de) Gereinigtes sr-p70 protein
EP0980427B1 (de) Verwendung von ulip proteinen zur diagnose und therapie von krebs und paraneoplastischen neurologischen syndromen
EP0874049B1 (de) Nukleinsäuren von CIITA Genen
EP0651801A1 (de) Polypeptide mit serotoninerger (5ht5a) rezeptor-aktivität, für sie kodierende nukleinsäuren und ihre verwendung
FR2742766A1 (fr) Sequences nucleotidiques, proteines, medicaments et agents diagnostics utiles dans le traitement du cancer
EP0828832A2 (de) $g(D)P62, SEINE VARIANTEN, DAFÜR KODIERENDE NUKLEINSÄUREN, UND DEREN VERWENDUNGEN IN GENTHERAPIE GEGEN KREBS
WO1996001898A1 (fr) Recepteur opioide kappa humain, acides nucleiques et utilisations
CA2275454A1 (fr) Polypeptides de la famille "basic helix-loop-helix" bhlh, sequences d'acides nucleiques correspondantes
CA2153162A1 (fr) Nouveaux polypeptides ayant une activite de recepteur serotoninergique, acides nucleiques codant pour ces polypeptides et utilisations
KR20230171424A (ko) 암의 치료를 위한 후성적 침묵
WO2001057209A2 (fr) Nouvelle famille de proteines, denommees atip, les sequences nucleiques codant pour lesdites proteines et leurs applications
CA2139431A1 (fr) Polypeptides ayant une activite de recepteur serotoninergique (5ht6), acides nucleiques codant pour ces polypeptides et utilisations
WO2000022120A1 (fr) Polypeptides (mbp1) capables d'interagir avec les mutants oncogeniques de la proteine p53
FR2784383A1 (fr) Polypeptides capables d'interagir avec les mutants oncogeniques de la proteine p53
FR2723749A1 (fr) Nouveau transporteur vesiculaire de l'acetylcholine
FR2747691A1 (fr) Acides nucleiques et proteines utiles a titre d'agent anticancereux et antiviral
FR2802944A1 (fr) Sequences nucleotidiques codant pour un polypeptide capable d'interagir avec des proteines des familles p300/cbp et rb
FR2772046A1 (fr) Sequences codant pour une proteine kin17 et leurs applications
WO2000071708A2 (fr) UTILISATION DE EF-Ts DANS LE CADRE DES HYPERPLASIES DES CELLULES MUSCULAIRES LISSES (CML)
CA2490017A1 (fr) Acide nucleique isole du 5'ntr du gene fgf-1 humain presentant une activite ires

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010226

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20030327

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20040602