EP0735889A1 - Nouveau gene suppresseur de tumeur - Google Patents
Nouveau gene suppresseur de tumeurInfo
- Publication number
- EP0735889A1 EP0735889A1 EP95906694A EP95906694A EP0735889A1 EP 0735889 A1 EP0735889 A1 EP 0735889A1 EP 95906694 A EP95906694 A EP 95906694A EP 95906694 A EP95906694 A EP 95906694A EP 0735889 A1 EP0735889 A1 EP 0735889A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- protein
- nuc
- vector
- cells
- cell
- 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- Withdrawn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
- 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
- C07K14/4736—Retinoblastoma protein
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- Cancer genes are broadly classified into “oncogenes” which, when activated, promote tumorigenesis, and “tumor suppressor genes” which, when damaged, fail to suppress tumorigenesis. While these classifications provide a useful method for conceptualizing tumorigenesis, it is also possible that a particular gene may play differing roles depending upon the particular allelic form of that gene, its regulatory elements, the genetic background and the tissue environment in which it is operating.
- the first class consists of mutated or otherwise aberrant alleles of normal cellular genes that are involved in the control of cellular growth or replication. These genes are the cellular protooncogenes. When mutated, they can encode new cellular functions that disrupt normal cellular growth and replication. The consequence of these changes is the production of dominantly expressed tumor phenotypes.
- the RB gene encodes a nuclear protein which is phosphorylated on both serine and threonine residues in a cell cycle dependent manner (Lee et al . f Nature , 329:642- 645 (1987) ; Buchkovich et al .. Call, 58:1097-105 (1989) ; Chen et al.. Cell. 58:1193-1198 (1989); DeCaprio et al. r Cell. 58:1085-1095 (1989)) .
- Rb exists in a hypophosphorylated state ( Goodrich et al .. Cell.
- Rb The molecular mechanisms by which Rb participates in these cellular activities has not been completely elucidated. A current model holds that Rb interacts with many different cellular proteins and may execute its functions through these complexes. If the function of Rb protein is to maintain cells at G0/G1 stage, Rb must "corral" and inactivate other proteins which are active and essential for entering Gl progression (Lee et al .. CSHSOB. LVI -211-217 (1991)) . This "corral" hypothesis is consistent with recent observations that an important growth-enhancing transcriptional factor, E2F-1, is tightly regulated by Rb in a negative fashion (Helin et al.. Cell. 70:337-350 (1992) ; Kaelin Cell.
- the present invention is also directed to the administration of wild-type H-NUC tumor suppressor gene or protein to suppress, eradicate or reverse the neoplastic phenotype in established cancer cells having no endogenous wild-type H-NUC protein.
- This invention demonstrated for the first time administration of wild-type H-NUC gene to established cancer cells to suppress or reverse the neoplastic phenotype or properties of established human cancer cells lacking wild-type H-NUC protein.
- This suppression of the neoplastic phenotype in turn suppressed or eradicated the abnormal mass of such cancer cells, i.e. tumors, which in turn can reduce the burden of such tumors on the animal which in turn can increase the survival of the treated animals.
- Figure 3 is the nucleotide (SEQ. I.D. NO.: 1) and predicted amino acid (SEQ. I.D. NO.: 2) sequences of the full length H-NUC cDNA and protein.
- FIG. 4B is an alignment of the amino acid sequences of the 9 TPR unit repeats (1-9) in nuc2+,-H- NUC and bimA proteins. conserveed residues are boxed. TPR unit repeat 6 of all three proteins contains a glycine in position 6. Gly6 in repeat 6 of nuc2 is thought to be essential.
- Figures 5A and 5B show that C-terminal TPR repeats of H-NUC bind to the RB protein.
- Figure 5A is a schematic of Gal4-H-NUC fusions used to determine binding domains. The Gal4 transactivation domain is fused to various H-NUC deletion mutants.
- AC-H-NUC is a recombinant human adenovirus containing the H-NUC tumor suppressor gene under control of the human CMV promoter.
- ACN is the same recombinant human adenovirus vector without the H-NUC tumor suppressor gene.
- H-NUC derivatives or equivalents such as H-NUC truncated protein, polypeptide or H-NUC peptides, having the biological activity of purified H-NUC protein.
- H-NUC derivatives refers to compounds that depart from the linear sequence of the naturally occurring proteins or polypeptides, but which have amino acid alterations, i.e., substitutions, deletions or insertions such that the resulting H-NUC derivative retains H-NUC biological activity.
- Biological activity or “biologically active” shall mean in one aspect having the ability to bind to the unphosphorylated retinoblastoma protein pllO 1 ⁇ .
- an isolated nucleic acid molecule of this invention is operatively linked to a promoter of RNA transcription.
- These nucleic acid molecules are useful for the recombinant production of H- NUC proteins and polypeptides or as vectors for use in gene therapy.
- Fab the fragment which contains a monovalent antigen-binding fragment of an antibody molecule produced by digestion with the enzyme papain to yield an intact light chain and a portion of one heavy chain;
- Anti-idiotypic peptides specifically reactive with the antibodies or biologically active fragments thereof also are provided by this invention.
- anti-idiotypic peptides are purified antibodies from one species that are injected into a distant species and recognized as foreign antigens and elicit a strong humoral immune response. For a discussion of general methodology, see Harlow and Lane, supra. incorporated herein by reference.
- the beads were boiled in SDS sample buffer and the immunoprecipitates were separated with 7.5% SDS-PAGE.
- the resulting immune complexes were boiled in 200 ⁇ l dissociation buffer I (20 mM Tris-Cl, pH 7.4, 50 mM NaCl, 1% SDS and 5 mM DTT) to denature the proteins.
- the denatured proteins were diluted with 200 ⁇ l dissociation buffer II (20 mM Tris-Cl, pH 7.4, 50 mM NaCl, 1% NP40 and 1% Na-deoxycholate) and re-immunoprecipitated with antibodies.
- C-49 is unable to bind the Ssp mutant, which lacks the C-terminal 160 amino acids of the RB protein, whereas T-antigen can bind, albeit with reduced affinity.
- the Ml deletion (amino acids 612-632) , which deletes part of the linker region between the two binding subdomains, is the only mutant able to bind both H-NUC and T-antigen.
- a similar but not identical region of the RB protein is required for binding both T-antigen and C-49.
- H-NUC was able to bind only unphosphorylated pllO 13 with an affinity similar to that of Gst-T, which served as a positive control.
- GST alone does not bind to any Rb protein (see Figure IA, lanes 2-4) .
- Lysis 250 buffer 250mM NaCl, 5mM EDTA, 50mM Tris (pH 8.0) , 0.1% NP40, ImM phenylmethylsulfonyl fluoride (PMSF) , 8 ug/ml of leupeptin and 8 ug/ml of antipain
- Lysates were clarified by centrigugation and diluted with 2 volumes of loading buffer (lOmM KH 2 P0 4 , pH6.2, ImM MgCl 2 , 0.5% NP40, ImM DTT, 10% glycerol) .
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (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)
Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17058693A | 1993-12-20 | 1993-12-20 | |
US170586 | 1993-12-20 | ||
PCT/US1994/014813 WO1995017198A1 (fr) | 1993-12-20 | 1994-12-20 | Nouveau gene suppresseur de tumeur |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0735889A1 true EP0735889A1 (fr) | 1996-10-09 |
EP0735889A4 EP0735889A4 (fr) | 1999-04-14 |
Family
ID=22620468
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95906694A Withdrawn EP0735889A4 (fr) | 1993-12-20 | 1994-12-20 | Nouveau gene suppresseur de tumeur |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0735889A4 (fr) |
JP (1) | JPH09510343A (fr) |
CN (1) | CN1138295A (fr) |
AU (1) | AU1517495A (fr) |
BR (1) | BR9408357A (fr) |
CA (1) | CA2178745A1 (fr) |
CZ (1) | CZ178396A3 (fr) |
FI (1) | FI962558A0 (fr) |
HU (1) | HUT74413A (fr) |
NO (1) | NO962596L (fr) |
NZ (1) | NZ278745A (fr) |
PL (1) | PL315172A1 (fr) |
SK (1) | SK76896A3 (fr) |
WO (1) | WO1995017198A1 (fr) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5747282A (en) * | 1994-08-12 | 1998-05-05 | Myraid Genetics, Inc. | 17Q-linked breast and ovarian cancer susceptibility gene |
CN1054399C (zh) * | 1997-11-07 | 2000-07-12 | 中国科学院上海生物化学研究所 | 一个与抗癌基因p53相作用的人类新基因p53bp3 |
AU771619B2 (en) | 1998-06-30 | 2004-04-01 | Genset S.A. | A nucleic acid encoding a retinoblastoma binding protein (RBP-7) and polymorphic markers associated with said nucleic acid |
AU774577B2 (en) * | 1999-07-05 | 2004-07-01 | Cropdesign N.V. | Plant proteins |
WO2001029229A1 (fr) * | 1999-10-18 | 2001-04-26 | Shanghai Bio Road Gene Development Ltd. | Nouveau polypeptide, proteine humaine 20 de liaison de retinoblastome et polynucleotide le codant |
CN1333255A (zh) * | 2000-07-07 | 2002-01-30 | 上海博德基因开发有限公司 | 一种新的多肽——人视网膜瘤结合蛋白19.91和编码这种多肽的多核苷酸 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4358535A (en) * | 1980-12-08 | 1982-11-09 | Board Of Regents Of The University Of Washington | Specific DNA probes in diagnostic microbiology |
-
1994
- 1994-12-20 EP EP95906694A patent/EP0735889A4/fr not_active Withdrawn
- 1994-12-20 BR BR9408357A patent/BR9408357A/pt not_active Application Discontinuation
- 1994-12-20 NZ NZ278745A patent/NZ278745A/en not_active IP Right Cessation
- 1994-12-20 WO PCT/US1994/014813 patent/WO1995017198A1/fr not_active Application Discontinuation
- 1994-12-20 CA CA002178745A patent/CA2178745A1/fr not_active Abandoned
- 1994-12-20 AU AU15174/95A patent/AU1517495A/en not_active Abandoned
- 1994-12-20 HU HU9601686A patent/HUT74413A/hu unknown
- 1994-12-20 SK SK768-96A patent/SK76896A3/sk unknown
- 1994-12-20 CN CN94194569A patent/CN1138295A/zh active Pending
- 1994-12-20 CZ CZ961783A patent/CZ178396A3/cs unknown
- 1994-12-20 PL PL94315172A patent/PL315172A1/xx unknown
- 1994-12-20 JP JP7517608A patent/JPH09510343A/ja active Pending
-
1996
- 1996-06-19 NO NO962596A patent/NO962596L/no not_active Application Discontinuation
- 1996-06-19 FI FI962558A patent/FI962558A0/fi unknown
Non-Patent Citations (2)
Title |
---|
No further relevant documents disclosed * |
See also references of WO9517198A1 * |
Also Published As
Publication number | Publication date |
---|---|
HUT74413A (en) | 1996-12-30 |
BR9408357A (pt) | 1997-08-26 |
FI962558A (fi) | 1996-06-19 |
AU1517495A (en) | 1995-07-10 |
WO1995017198A1 (fr) | 1995-06-29 |
CA2178745A1 (fr) | 1995-06-29 |
PL315172A1 (en) | 1996-10-14 |
SK76896A3 (en) | 1997-02-05 |
EP0735889A4 (fr) | 1999-04-14 |
FI962558A0 (fi) | 1996-06-19 |
CZ178396A3 (en) | 1997-03-12 |
HU9601686D0 (en) | 1996-08-28 |
NZ278745A (en) | 1997-09-22 |
NO962596L (no) | 1996-08-19 |
NO962596D0 (no) | 1996-06-19 |
JPH09510343A (ja) | 1997-10-21 |
CN1138295A (zh) | 1996-12-18 |
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Legal Events
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Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
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