Figure 80-1 Induction of p53 by the DNA damage and oncogene checkpoints. In response to noxious stimuli, p53 and mdm2 are phosphorylated by the ataxia telangiectasia mutated (ATM) and related ATR serine/threonine kinases, as well as the immediated downstream checkpoint kinases, Chk1 and Chk2. This causes dissociation of p53 from mdm2, leading to increased p53 protein levels and transcription of genes leading to cell cycle arrest (p21Cip1/Waf1) or apoptosis (., the proapoptotic Bcl-2 family members Noxa and Puma). Inducers of p53 include hypoxia, DNA damage (caused by ultraviolet radiation, gamma irradiation, or chemotherapy), ribonucleotide depletion, and telomere shortening. A second mechanism. | Chapter 080. Cancer Cell Biology and Angiogenesis Part 3 Figure 80-1 1 ONA Damage Checkpoint 2 Oncogene Checkpoint Sourx Fiud A3 Mipt DL 6rtu u ld E SL Longo DL Jjrrnioti JU Loicilto Jl Htrrixtm f Pnrnipi s of nt-tfnti 17th Edition i http isrn didn .com Copyright Th- McGr -H It Comppnuij Inc All right rè ru d. Induction of p53 by the DNA damage and oncogene checkpoints. In response to noxious stimuli p53 and mdm2 are phosphorylated by the ataxia telangiectasia mutated ATM and related ATR serine threonine kinases as well as the immediated downstream checkpoint kinases Chk1 and Chk2. This causes dissociation of p53 from mdm2 leading to increased p53 protein levels and transcription of genes leading to cell cycle arrest p21Cip1 Waf1 or apoptosis . the proapoptotic Bcl-2 family members Noxa and Puma . Inducers of p53 include hypoxia DNA damage caused by ultraviolet radiation gamma irradiation or chemotherapy ribonucleotide depletion and telomere shortening. A second mechanism of p53 induction is activated by oncogenes such as Myc which promote aberrant G1 S transition. This pathway is regulated by a second product of the Ink4a locus p19ARF which is encoded by an alternative reading rame of the same stretch of DNA that codes for p16Ink4a. Levels of ARF are upregulated by Myc and E2F and ARF binds to mdm2 and rescues p53 from its inhibitory effect. This oncogene checkpoint leads to the death or senescence an irreversible arrest in G1 of the cell cycle of renegade cells that attempt to enter S phase without appropriate physiologic signals. Senescent cells have been identified in patients whose premalignant lesions harbor activated oncogenes for instance dysplastic nevi that encode an activated form of BRAF see below demonstrating that induction of senescence is a protective mechanism that operates in humans to prevent the outgrowth of neoplastic cells. Acquired mutation in p53 is the most common genetic alteration found in human cancer 50 germline mutation in .
