Apoptosis is a genetically controlled mechanism of cell death that is essential for the elimination of unwanted cells during normal development and for the maintenance of tissue homeostasis. One of the major apoptosis signaling pathways involves the p53 tumour suppressor. Tumor protein p53 is a nuclear transcription factor that regulates the expression of a wide variety of genes involved in apoptosis, growth arrest or senescence in response to genotoxic or cellular stress. There are four conserved domains in p53: N-terminal domain, which is required for transcriptional transactivation, a sequence-specific DNA binding domain, a tetramerization domain near the C-terminal end and a C-terminal domain that interacts directly with single stranded DNA. Having a short half-life, p53 is normally maintained at low levels in unstressed mammalian cells by continuous ubiquitylation and subsequent degradation by the 26S Proteasome. Nonphosphorylated p53 is ubiquitylated by the MDM2 (Mouse Double Minute-2) ubiquitin ligase. When the cell is confronted with stress like DNA damage, Hypoxia, Cytokines, metabolic changes, Viral infection, or Oncogenes, however, p53 ubiquitylation is suppressed and p53 is stabilized and accumulates in the nucleus. The N-terminus of p53 may be heavily phosphorylated, whereas the C-terminus may be phosphorylated, acetylated or sumoylated. The ability of p53 to elicit diverse regulatory functions is likely to depend on its phosphorylation pattern, which is conformation dependent. p53 phosphorylation is mediated by several cellular kinases including Chks (Checkpoint Kinases), CSNK1-Delta (Casein Kinase-1-Delta), CSNK2 (Casein Kinase-2), PKA (Protein Kinase A), CDK7 (Cyclin-Dependent Kinase-7), DNA-PK (DNA-Activated- Protein Kinase), HIPK2 (Homeodomain-Interacting Protein Kinase-2) and JNK (Jun NH2-terminal kinase). The main Kinases involved in p53 phosphorylation include Chk1 (Cell Cycle Checkpoint Kinase-1) and Chk2 (Cell Cycle Checkpoint Kinase-2). In response to DNA Damage Chk1 and Chk2, activated by ATR (Ataxia-Telangiectasia and Rad3 Related) and ATM Ataxia Telangiectasia Mutated Gene) respectively, phosphorylates p53. Chk2 can phosphorylate p53 on Ser20, which prevents MDM2 binding and results in p53 stabilization. ATM can also phosphorylate p53 on Ser15, which is required for activation of p53 as a transcription factor and may act synergistically with Ser20 phosphorylation. Once activated p53 binds, as a tetramer, to a p53-binding site. In doing so, it activates expression of downstream genes leading to programmed cell death and/or cell cycle arrest, thus functioning as a tumor suppressor. p53 promotes apoptosis through multiple mechanisms, including transactivation of specific target genes, down-regulation of a distinct set of genes, and transcription-independent mechanisms (Ref. 1 & 2). References 1.The role of p53 in apoptosis. Amaral JD, Xavier JM, Steer CJ, Rodrigues CM. Discov Med. 2010 Feb;9(45):145-52. 2.p53 Family: Role of Protein Isoforms in Human Cancer. Wei J, Zaika E, Zaika A. J Nucleic Acids. 2012;2012:687359. Epub 2011 Oct 9. 3.Placental apoptosis in health and disease. Sharp AN, Heazell AE, Crocker IP, Mor G. Am J Reprod Immunol. 2010 Sep;64(3):159-69. 4.p53-mediated delayed NF-?B activity enhances etoposide-induced cell death in medulloblastoma. Meley D, Spiller DG, White MR, McDowell H, Pizer B, Sée V. Cell Death Dis. 2010 May 13;1:e41. 5.p53 and the regulation of hepatocyte apoptosis: implications for disease pathogenesis. Amaral JD, Castro RE, Steer CJ, Rodrigues CM. Trends Mol Med. 2009 Nov;15(11):531-41. Epub 2009 Oct 12. Davies L, Spiller D, White MR, Grierson I, Paraoan L. Cell Death Dis. 2011 Mar 31;2:e136. Zhang XP, Liu F, Wang W. J Biol Chem. 2010 Oct 8;285(41):31571-80. Epub 2010 Aug 4. 8.PUMA, a potent killer with or without p53. Yu J, Zhang L. Oncogene. 2008 Dec;27 Suppl 1:S71-83. 9.Noxa: at the tip of the balance between life and death. Ploner C, Kofler R, Villunger A. Oncogene. 2008 Dec;27 Suppl 1:S84-92. 10.p53: the attractive tumor suppressor in the cancer research field. Ozaki T, Nakagawara A. J Biomed Biotechnol. 2011;2011:603925. Epub 2010 Dec 6. 11.Post-translational myristoylation: Fat matters in cellular life and death. Martin DD, Beauchamp E, Berthiaume LG. Biochimie. 2011 Jan;93(1):18-31. Epub 2010 Nov 5. 12.Oscillations of the p53-Akt network: implications on cell survival and death. Wee KB, Surana U, Aguda BD. PLoS One. 2009;4(2):e4407. Epub 2009 Feb 6. 13.Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. Degtyarev M, De Mazière A, Orr C, Lin J, Lee BB, Tien JY, Prior WW, van Dijk S, Wu H, Gray DC, Davis DP, Stern HM, Murray LJ, Hoeflich KP, Klumperman J, Friedman LS, Lin K. J Cell Biol. 2008 Oct 6;183(1):101-16. 14.Mutant p53 gain-of-function in cancer. Oren M, Rotter V. Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a001107. Malkin D. Genes Cancer. 2011 Apr;2(4):475-84.
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