Mouse models of p53 functions

Studies in mice have yielded invaluable insight into our understanding of the p53 pathway. Mouse models with activated p53, no p53, and mutant p53 have queried the role of p53 in development and tumorigenesis. In these models, p53 is activated and stabilized via redun-dant posttranslational modifications. On activation, p53 initiates two major responses: inhi-bition of proliferation (via cell-cycle arrest, quiescence, senescence, and differentiation) and induction of apoptosis. Importantly, these responses are cell-type and tumor-type-specific. The analysis of mutant p53 alleles has established a gain-of-function role for p53 mutants in metastasis. The development of additional models that can precisely time the oncogenic events in single cells will provide further insight into the evolution of tumors, the importance of the stroma, and the cooperating events that lead to disruption of the p53 pathway. Ultimately, these models should serve to study the effects of novel drugs on tumor response as well as normal homeostasis. The p53 tumor suppressor is a master regula-tor of transcription, positively and nega-tively regulating a plethora of genes with roles in cell-cycle arrest, quiescence, senescence, dif-ferentiation, and apoptosis. Because these activ-ities are so potent at preventing cell proliferation or causing cell death, p53 is normally kept at very low levels. p53 levels and activity increase dramatically in response to DNA damage, on-cogenic stress, and other stimuli that are viewed by a cell as anomalous. Animal models have allowed us to examine the in vivo effects of p53 activation, p53 deletion, and the role of p53 missense mutations in tumorigenesis. This article focuses on the important role of animal models in deciphering p53 activities and their implications for survival, development, and tumorigenesis