The role of p53-mediated apoptosis as a crucial anti-tumor response to genomic instability: lessons from mouse models.
Genomic instability is a major force driving human cancer development. A cellular safeguard against such genetic destabilization, which can ensue from defects in telomere maintenance, DNA repair, and checkpoint function, is activation of the p53 tumor suppressor protein, which commonly responds to these DNA damage signals by inducing apoptosis. If, however, p53 becomes inactivated, as is typical of many tumors and pre-cancerous lesions, then cells with compromised genome integrity pathways survive inappropriately, and the accrual of oncogenic lesions can fuel the carcinogenic process. Studies of mouse models have been instrumental in providing support for this idea. Mouse knockouts in genes important for telomere function, DNA damage checkpoint activation and DNA repair - both non-homologous end joining and homologous recombination - are prone to the development of genomic instability. As a consequence of these DNA damage signals, p53 becomes activated in cells of these mutant mice, leading to the induction of apoptosis, sometimes at the expense of organismal viability. This apoptotic response can be rescued through crosses to p53-deficient mice, but has dire consequences: mice predisposed to genomic instability and lacking p53 are susceptible to tumorigenesis. Thus p53-mediated apoptosis provides a crucial tumor suppressive mechanism to eliminate cells succumbing to genomic instability.
Attardi
Laura D
LD
Stanford University School of Medicine, Departments of Radiation Oncology and Genetics, CCSR South, Room 1255, 269 Campus Drive, Stanford, CA 94305-5152, USA.
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004249:DNA Damage; D042822:Genomic Instability / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D051379:Mice; D023421:Models, Animal; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D016615:Telomere / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D006657:Histones; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse