Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving viable micro-organism
Patent
1997-06-11
1999-03-16
Degen, Nancy
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving viable micro-organism
4353201, 530350, 536 235, C07H 1447, C07H 2100, C12N 1585, C12Q 102
Patent
active
058828800
DESCRIPTION:
BRIEF SUMMARY
This application is a national phase filing under 35 U.S.C. .sctn.371 of application PCT/US95/12445 filed Oct. 11, 1995.
FIELD OF THE INVENTION
The present invention relates to genes and polynucleotides which regulate the cell cycle and/or programmed cell death processes (apoptosis), and in particular to checkpoint genes and proteins, related polynucleotides and a method for isolating these genes.
BACKGROUND OF THE INVENTION
Cancer cells typically display abnormal genomes with aneuploidy and chromosomal rearrangements, including high frequency gene amplification at late stages of tumor progression. The existence of a number of human cancer prone genetic diseases with defects in DNA repair, whose non-tumorous cells display unstable karyotypes provides strong evidence that genomic instability is heritable, and associated with a predisposition to cancer.
The development of a malignant cell is a multistep process. The spontaneous rate of mutation in normal somatic cells is less than 10.sup.-5 mutation/gene/generation. Thus, the accumulation of a number of genetic changes by a clone of cells would be more likely to occur if an early step produces a genetically unstable cell. Eukaryotes have generated a variety of mechanisms for limiting the formation of abnormal, heritable genetic changes. These include mechanisms for maintaining fidelity of DNA replication and segregation, mechanisms for DNA repair, and checkpoint genes for cell cycle progression or for programmed cell death (apoptosis).
It has been assumed that one mechanism leading to genomic instability could be a defect in a DNA repair pathway. The recent findings of a defective mismatch repair in hereditary non-polyposis colorectal cancer confirmed that assumption.
Another possible mechanism for generating genomic instability is perturbation of the normal cell cycle control. At least two stages in the cell cycle are regulated in response to DNA damage--the G.sub.1 -S and the G.sub.2 -M phase transitions. These transition serve as checkpoints at which cells delay cell cycle progression, presumably to allow repair of damage before the cell enters either replicative DNA synthesis (G.sub.1 -S), when damage could be perpetuated, or before the cell enters mitosis (G.sub.2 -M), when chromosomal breaks would result in the loss of genetic material.
This possibility was initially supported by features of Barrett's esophagus, a cancer-prone syndrome, which shows a sequential appearance of high S and/or high G.sub.2 phase populations, followed by the emergence of aneuploid cells and subsequently the development of tumors. The demonstration by Weinert and Hartwell that mutations in the yeast radiation-monitoring G.sub.2 -M checkpoint gene RAD9 (Hartwell and Weinert, 1989) and in the G.sub.1 -S checkpoint genes RAD5 and RAD51 lead to increased spontaneous chromosome loss further supported this supposition. These observations led Hartwell to propose that some of the tumor suppressor genes actually operate as cell cycle checkpoint genes. The prediction was soon proven correct when Kastan and colleagues demonstrated that human p53 is a G.sub.1 -S checkpoint gene which prevents entry into S phase when DNA is damaged by irradiation (Kastan et al., 1991; Kuerbitz et al., 1992). This result becomes more noteworthy when we take into account that the loss or mutation of the p53 gene is the most common alteration found in sporadic, non familial cancers of either solid tumor or hematopoietic ones. Furthermore, p53 also protects the cell from genomic instability reflected in gene amplification and acts as a checkpoint by activating an inhibitor (p21) of G.sub.1 -S phase transition (El-Deiry et. al., 1993; Dulic et. al., 1994).
Another example of the involvement of aberrations in cell cycle control with human cancers is the recognition that an inhibitor (p16) of cyclin-dependent kinase 4 is encoded by a tumor suppressor gene, which is defective in various human cancers including melanoma.
A further demonstration of the link between human cancers and the cell cycle machinery h
REFERENCES:
patent: 5585479 (1996-12-01), Hoke et al.
Gewirtz et al. Facilitating olignucelotide delivery: Helping antisense deer on its promise. Proc. Natl. Acad. Sci. USA 93: 3161-3163, Apr. 1996.
Zon et al. "Phosphorothioate oligonucleotides" in Oligonucleotides and Analogues: A Practical Approach, Eckstein, ed. IRL Press, New York, pp. 87-108, 1991.
Int'l Search Report (2 pages)--WO 96/11562.
Kuerbitz, Steven J., et al., "Wild-type p53 is a Cell Cycle Checkpoint Determinant Following Irradiation," Proc. Natl. Acad. Sci. USA, vol. 89, pp. 7491-7495, 1992.
Hillier, L., "The WashU-Merck EST Project" (unpublished).
Jeggo, P.A., et al., "Cloning Human DNA Repair Genes," Int. J. Radiat. Biol., vol. 66, No. 5, pp. 573-577, 1994.
Canaani, Dan et al., Immortalization of Xeroderma . . . Replication, Somatic Cell and Mol. Gen., vol. 12, No. 1, 1986, pp. 13-20.
Stark, Merav et al., Ultraviolet Light-Resistant . . . Repair-Proficient, Biochem. and Biophys. Res. Comm., vol. 162, No. 3, 1989, pp. 1351-1356.
Naiman, Tova et al., A Hypodiploid Karyotype . . . Complements, Cancer Genet Cytogenet 40:65-71, 1989, pp. 65-71.
Clarke, A.R. et al., Thymocyte Apoptosis Induced . . . Pathways, Nature, vol. 362, 1993, pp. 849-852.
Dulic, Vjekoslav et al., p53-Dependent Inhibition of Cyclin-Dependent . . . Arrest, Cell, vol. 76, 1994, pp. 1013-1023.
El-Deiry, Wafik S. et al., WAF-1, a Potential . . . Suppression, Cell, vol. 75, 1993, pp. 817-825.
Hartwell, Leland H. et al., Checkpoints: Controls . . . Events, Science, vol. 246, 1989, pp. 629-634.
Jacobson, Michael D. et al., Bcl-2 Blocks Apoptosis . . . DNA, Nature, vol. 361, 1993, pp. 365-369.
Lowe, Scott W. et al., p53 is Required for Radiation-Induced . . . Thymocytes, Nature, vol. 362, 1993 pp. 847-849.
Kastan, Michael B. et al., Participation of p53 . . . Damage, Cancer Res. 51, 1991, p-p. 6304-6311.
Pereira-Smith, Olivia M. et al., Genetic Analysis of . . . Groups, Proc. Natl. Acad. Sci. USA, vol. 85, 1988, pp. 6042-6046.
Takeda, Jun. et al., A Molecular Inventory of . . . Clones, Human Mol. Gen 2, 1993, pp. 1793-1798.
Teitz, Tal et al., Isolation by Polymerase Chain . . . Cells, Gene, vol. 87, 1990, pp. 295-298.
Teitz, Tal et al., Complementation of the UV-Sensitive . . . cDNA, Proc. Natl. Acad, Sci. USA, vol. 84, 1987, pp. 8801-8804.
Yonish-Rouach, Elisheva, Wild-Type p53 . . . Interleukin-6, Nature, vol. 352, 1991, pp. 345-347.
Degen Nancy
Larson Thomas G.
Ramot University Authority for Applied and Industrial Developmen
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