Unformatted text preview: ral cell cycle
checkpoints halt cell cycle progression in response to damaged DNA,
allowing time for the damage to be repaired. In mammalian cells, a major
pathway leading to cell cycle arrest in response to DNA damage is mediated by the transcription factor p53. The ATM and Chk2 protein kinases,
which are activated by DNA damage, phosphorylate and stabilize p53. The
resulting increase in p53 leads to transcriptional activation of p53 target
genes. These include the Cdk inhibitor p21, which inhibits Cdk2/cyclin E
complexes, halting cell cycle progression in G1 (see Figure 16.20). However,
activation of p53 by DNA damage can also lead to apoptosis (Figure 17.10).
The induction of apoptosis by p53 results, at least in part, from transcriptional activation of genes encoding the BH3-only proapoptotic Bcl-2 family
members PUMA and Noxa. Increased expression of these BH3-only proteins leads to activation of Bax and Bak, release of cytochrome c from mitochondria, and activation of caspase-9. Thus p53 mediates both cell cycl...
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