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What is p53 ?
After the identification of the p53 protein and the subsequent cloning of p53 genes from several species, early observations suggested that p53 may function as an oncogene, because overexpression of p53 appeared to cause oncogenic transformation of cells. In the late 1980s, however, several critical discoveries defined the normal function of p53 to be anti-oncogenic. Wild-type p53 genes, when introduced into cells, were found to be growth suppressive. The screening of DNA from colon cancer patients revealed that p53 mutations occur with unusually high frequency in tumor tissue, an observation that was extended to most of the other major forms of human cancer. Indeed, members of Li-Fraumeni cancer-prone families were shown to carry germ-line p53 mutations. The importance of these observations was underscored by the finding that mice that are homozygous null for p53, although developmentally competent, are highly predisposed to tumors.
The functional character of the p53 protein was determined by experiments showing that p53 contains a strong transcriptional activation domain within its amino terminus and that it is a tetrameric, sequence-specific DNA-biding protein with a defined cognate binding site containing two copies of the 10-mer (5'-RRRCA/TT/AGYYY-3'). Although the p53 protein acts as a transcriptional activator of genes containing p53-binding sites, it is also capable of strongly inhibiting transcription from many genes lacking p53-binding sites. Several oncogenic DNA viruses express viral gene products that associate with and inhibit the trans-activation function of p53, notably SV40 large T antigen, the adenovirus E1B 55-kD protein, and the E6 protein of oncogenic forms of human papillomavirus (HPV E6). In cells, p53 can associate with a 90-kD protein, identified as the product of the mdm-2 oncogene, which is amplified in some types of tumors. When bound to mdm-2, p53 can no longer function as an activator of transcription.
p53 plays multiple roles in cells. Expression of high levels of wild-type (but not mutant) p53 has two outcomes: cell cycle arrest or apoptosis. The observation that DNA-damaging agents induce levels of p53 in cells led to the definition of p53 as a checkpoint factor, akin, perhaps, to the product of the fad9 gene in yeast. While dispensable for viability, in response to genotoxic stress, p53 acts as an "emergency brake" inducing either arrest or apoptosis, protecting the genome from accumulating excess mutations. Consistent with this notion, cells lacking p53 were shown to be genetically unstable and thus more prone to tumors.
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发表于 2003-11-30 02:41:00
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