Cell cycle regulation by the tumor suppressor p53
Presented is a comprehensive examination of the role of p53 in the DNA damage response. A special focus is placed on the involvement of the cyclin-dependent kinase inhibitor p21CIP1, a p53 target gene. Using two independent isogenic systems in U2OS cells, the regulation of the response to genotoxic stress by both p53 and p21 are examined. Data presented herein indicate that cells lacking either protein are highly sensitive to DNA damaging agents and undergo apoptosis following prolonged exposure to genotoxic stress. The presence of p53 and p21 enables cells to stably arrest in response to DNA damage and is essential for the restriction of entry into mitosis. Furthermore, it is demonstrated that cells with p53, but not p53-ablated cells, are able to recover from short exposures to DNA damaging agents. Additionally, the characterization of a novel p53 response element in the human PIG3 promoter is reported and the transactivation function of two human tumor-derived p53 mutants on various pro-apoptotic promoters is characterized.