Could p53 be a target for therapeutic suppression?
The function of p53 has been traditionally viewed in the context of its tumor suppressor activity. In fact, the p53-dependent growth arrest and apoptosis, occurring in response to a variety of stimuli, act to protect the organism from cancer by eliminating potential tumor precursors. However, the same functions of p53 could determine severe damage of normal tissues as a consequence of genotoxic stress associated with anti-tumor therapy. This makes p53 a potential target for therapeutic suppression with the purpose of rescuing normal tissues from the side effects of cancer treatment. We analyze the accumulated information regarding the role of p53 in acute and long-term consequences of genotoxic stress in vivo. Comparison of p53 wild type and p53-deficient mice indicates that p53, in fact, determines massive apoptosis occurring shortly after gamma irradiation in radiosensitive tissues. Sites of apoptosis match the tissue-specific pattern of p53 mRNA expression indicating that p53 regulation at mRNA level is a determinant of acute radiosensitivity of tissues. In the hematopoietic system, radiation-induced death of both differentiating and stem cells strongly depends on p53, suggesting that p53 suppression would decrease damage and promote faster recovery of hematopoiesis after anti-cancer therapy. However, p53 does not effect the recovery of radiosensitive epithelia since their stem cells, in contrast to differentiating cells, die in a p53-independent manner. The validity and potential complications of therapeutic suppression of p53 in cancer treatment and under other stressful conditions are discussed in relation to the p53 functions in normal development.
Komarova
E A
EA
Department of Molecular Genetics, University of Illinois at Chicago 60607, USA.
Gudkov
A V
AV
D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence; D004622:Embryo, Mammalian / Q000528:radiation effects; D005314:Embryonic and Fetal Development; D005720:Gamma Rays; D016158:Genes, p53; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013234:Stem Cells / Q000166:cytology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D006133:Growth Substances; D016159:Tumor Suppressor Protein p53