P53: A Cell Cycle Regulator Activated by DNA Damage

Abstract

Publisher Summary The chapter focuses on p53 —that is, a cell cycle regulator activated by deoxyribonucleic acid (DNA) damage. Mutations in the p53 tumor-suppressor gene occur at high frequency in a large variety of human tumors. These mutations include deletions of the entire gene, leading to complete loss of p53 expression, and missense point mutations that give rise to mutant p53 proteins lacking wild-type (WT) p53 activity. The high frequency of p53 alterations in human cancer suggests that this gene plays a critical role in the normal control of cell growth. A number of biological and biochemical functions have now been ascribed to WT p53 . Importantly, mutant p53 proteins derived from human tumors are defective in some of these functions, suggesting that such functions are relevant for p53 -mediated growth control and tumor suppression. This chapter reviews some of the recent progress in the exciting p53 field and proposes a model for the activation of p53 in response to DNA damage. The expression of exogenous WT p53 in various transformed cells carrying mutant p53 or completely lacking p53 inhibits cell proliferation. Experiments using replication of viral DNA as a model system have indicated that p53 may fulfill a role in the control of DNA replication. The common association between the viral oncoproteins and p53 represents a remarkable case of convergent evolution and provides strong evidence that p53 is a critical cell cycle regulator. P53 is normally an unstable protein with a half-life of 15–30 min. As a result, its levels in normal cells are almost undetectable and probably insufficient to suppress growth.