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Apoptosis: p53 Inhibitors
 | | | p53 is a potent transcription factor that upon activation either represses transcription of a set of genes involved in stimulating cell growth or activate yet another set of genes involved in cell cycle control. It is a phosphoprotein of about 390 amino acids consists of four domains: a highly charged acidic region of about 75 to 80 residues, a hydrophobic proline-rich domain (position 80 to 150), a central region (from 150 to about 300), and a highly basic C-terminal region.
p53 is phosphorylated at many sites by stress-activated protein kinases, DNA Protein kinase, casein kinase I and II, and cyclin-dependent kinases. When normal mammalian cells are subjected to stress signals (e.g. hypoxia, radiation, chemotherapeutic drugs) p53 is activated and its ubiquitin-dependent degradation is blocked. The resulting increase in p53-dependent gene transcription leads to the p53-mediated induction of programmed cell death and/or cell cycle arrest. Activation of p53 can result in cell cycle arrest, presumably to allow for DNA repair to occur before replication or mitosis. In some cell types, however, p53 activation results in apoptosis as means of eliminating irreparably damaged cells. The final outcome of p53 activation depends on many factors, and is mediated largely through the action of downstream effectors genes transactivated by p53. Functional p53 is thought to provide a protective effect against tumor growth and a loss of p53 function is considered as a key step in the neoplastic cascade. In addition, the function of p53 is critical to the way that many cancer treatments kill cells since radiotherapy and chemotherapy act in part by triggering cell suicide in response to DNA damage. A successful response to therapy is greatly reduced in tumors where mutant p53 is present, and these tumors are often very difficult to treat. | | | | | | | p53 Inhibitors | |
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