I. Field of the Invention
The present invention relates to the fields of oncology, genetics and molecular biology. More particular the invention relates to the identification, on human chromosome 10, of a p53-related tumor suppressor gene designated as Killin.
II. Related Art
Oncogenesis is a multistep biological process, which is presently known to occur by the accumulation of genetic damage. On a molecular level, the process of tumorigenesis involves the disruption of both positive and negative regulatory effectors (Weinberg, 1989). The molecular basis for human colon carcinomas has been postulated, by Vogelstein and coworkers (1990), to involve a number of oncogenes, tumor suppressor genes and repair genes. Similarly, defects leading to the development of retinoblastoma have been linked to another tumor suppressor gene (Lee et al., 1987). Still other oncogenes and tumor suppressors have been identified in a variety of other malignancies. Unfortunately, there remains an inadequate number of treatable cancers, and the effects of cancer are catastrophic—over half a million deaths per year in the United States alone.
p53 is the most frequently mutated, disrupted, and/or allelically lost tumor suppressor gene in human cancer, and it has been a focal point for intensive cancer research (Levine, 1997; Vogelstein et al., 2000; Vousden and Prives, 2005). Functionally, p53 works as a sequence dependent transcription factor, which upon activation by genotoxic stresses such as DNA damages regulates the expression of a set of target genes that are involved in cell growth control and apoptosis (El-Deiry, 1998; Yu et al., 1999; Vousden and Lu, 2002; Liang and Pardee, 2003). In contrast to a large number of p53 target genes that were implicated in cell apoptosis, activation of cell cycle arrest at G1 by p53 results predominantly from the induction of p21 (Deng et al., 1995), whereas p21 as well as GADD45 and 14-3-3 proteins were also shown to be involved in G2-M arrest (Taylor and Stark, 2001). Among the known p53 target genes implicated in apoptosis, a family of Bcl-2 related genes, such as bax, puma and noxa, are the best characterized and thought to work through a mitochondria-dependent death pathway (Yu and Zhang, 2005).
Through a genetic approach using somatic gene knockout strategy, it was shown that cellular choice between growth arrest and death upon p53 activation appears to depend on at least two factors. For cell types that undergo p53-mediated G1 arrest, elimination of p21 sensitizes cells to die (Polyak et al., 1996; Yu et al., 2003). In such cases, p21 clearly plays a protective role in apoptosis. In cell types that are prone to apoptosis upon p53 activation, transacting death-inducing factors are dominant over p21-mediated protection (Polyak et al., 1996; Yu et al., 2003). In the case of p21-mediated G1 arrest which protects cells from p53 induced apoptosis, one possible explanation could be that the apoptosis initiating event(s) require cells to enter S-phase. Supporting evidence for such S-phase-coupled apoptosis include findings that forced S-phase entry by unrestricted E2F activity can trigger the activation of caspases and apoptosis (Nahle et al., 2002; Gottifredi and Prives, 2005). Conceivably, DNA damage can happen to cells at any phase during the cell cycle. The induction of either p21 in cells at G1, or p21, GADD45 and 14-3-3 at G2/M phase by p53 will lead to growth arrest at the respective cell cycle phases. However, little is known about p53-mediated checkpoint control during S-phase where cells would run the highest risk of incorporating mutations after sustained DNA damage. It is logical that apoptosis would be the best choice for eliminating these cells. summary of the invention
USPTO Backgrounds
USPTO Backgrounds