The p53 Signaling Pathway

The tumor-suppressor protein p53 exhibits sequence-specific DNA-binding, directly interacts with various cellular and viral proteins, and induces cell cycle arrest in response to DNA damage. In response to signals generated by a variety of genotoxic stresses, e.g, UV irradiation or DNA damage, p53 is expressed and undergoes post-translational modification that results in its accumulation in the nucleus. The p53-dependent pathways help to maintain genomic stability by eliminating damaged cells either by arresting them permanently or through apoptosis. For example, g-irradiation activates p53 to turn on the transcription of p21^CIP1, which, in turn, binds to and inhibits cyclin-dependent kinases, causing hypophosphorylation of retinoblastoma (Rb), thus preventing the release of E2F and blocking the G₁-S transition. Some of the cellular effects of p53 can be blocked by the deregulated expression of c-Myc, Bcl-2, or E2F. p53 activity is controlled through an autoregulatory loop involving Mdm2. The binding of Mdm2 to p53 targets p53 for degradation and inhibits p53-induced cell-cycle arrest and apoptosis.

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References:

Gu, J., et al., Identification of a sequence element from p53 that signals for Mdm2-targeted degradation. Mol. Cell Biol., 20, 1243-1253 (2000).

Jimenez, G.S., et al., p53 regulation by post-translational modification and nuclear retention in response to diverse stresses. Oncogene, 18, 7656-7665 (1999).

King, K.L., and Cidlowski, J.A., Cell cycle regulation and apoptosis. Annu. Rev. Physiol., 60, 601-617 (1998).