p53 at the Crossroads Between Stress Response Signaling and Tumorigenesis: From Molecular Mechanisms to Therapeutic Opportunities

LUCIANA E. GIONO; M. FÁTIMA LADELFA; MARTÍN MONTE

Stress Response Pathways in Cancer

Springer Netherlands

Año: 2015; p. 51 - 73

The p53 tumor suppressor is a transcription factor that integrates signals from numerous stress-activated signaling pathways and regulates the expression of specific target genes. p53 activation triggers a variety of cellular responses that ensure tumor suppression, including cell cycle arrest, apoptosis and senescence. In addition, p53 tumor suppressive activity also involves the maintenance of cellular homeostasis through the regulation of metabolic pathways and the protection of stemness. Mutation of p53 protein or inactivation of the p53 pathway is the most frequent alteration found in human cancer. Loss of p53 function leads to tumorigenesis and is associated with poor prognosis and therapy resistance in cancer patients. Moreover, mutant p53 often exhibits gain of function activities that contribute to the tumoral phenotype. Over 30 years of basic research on p53 structure and function have placed p53 at the center of cancer investigation. Numerous cellular and mouse models have demonstrated that restoration of p53 function may stop tumor progression or even promote tumor regression. Now, these observations lead to the development of multiple anti-cancer therapeutic strategies that rely on activation of wild-type p53 or reactivation of mutant p53, as well as other p53-based approaches. Rational drug design and functional screenings have allowed for the identification of small molecule compounds, some of which are currently being tested in clinical trials.