AKT1, AKT2, AKT3, APAF1, ATM, ATR, BAX, BBC3, BCL2, BDNF, BID, BMP2, BMP4, BMP7, CASP3, CASP6, CASP8, CASP9, CHEK1, CHEK2, CTGF, CXCL12, CYCS, EGF, EGFR, FAS, FASLG, FGF1, FGF2, FGFR1, FGFR2, FGFR3, FLT1, FLT4, GH1, GLG1, HBEGF, HGF, IGF1, IGF1R, IGF2, IGF2R, IL2, IL2RA, IL6, KDR, KIT, KITLG, MDM2, MET, NGF, NGFR, NRG1..., NRP1, NRP2, NTRK1, NTRK2, NTRK3, OGFR, P53AIP1, PDGFB, PDGFRA, PDGFRB, PERP, PIK3C2A, PIK3C2B, PIK3C2G, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PMAIP1, PTEN, TGFA, TGFB1, TGFB2, TGFBR1, TGFBR3, TIMP1, TIMP2, TIMP3, TNFRSF10B, TNFSF10, TP53, TYMP, VEGFA, VEGFC
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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 t ...umor 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. Non-phosphorylated p53 is ubiquitylated by the MDM2 (Mouse Double Minute-2) ubiquitin ligase. p53 ubiquitylation is suppressed when the cell is confronted with stress like DNA damage, Hypoxia, cytokines, metabolic changes, Viral infection, or Oncogenes. Subsequently, 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. 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, phosphorylate 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.
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