Could p53 be a target for therapeutic suppression?

The function of p53 has been traditionally viewed in the context of its tum or suppressor activity. In fact, the p53-dependent growth arrest and apopto sis, occurring in response to a variety of stimuli, act to protect the orga nism from cancer by eliminating potential tumor precursors. However, the sa me functions of p53 could determine severe damage of normal tissues as a co nsequence of genotoxic stress associated with anti-tumor therapy. This make s p53 a potential target for therapeutic suppression with the purpose of re scuing normal tissues from the side effects of cancer treatment. We analyze the accumulated information regarding the role of p53 in acute and long-te rm consequences of genotoxic stress in vivo. Comparison of p53 wild type an d p53-deficient mice indicates that p53, in fact, determines massive apopto sis occurring shortly after gamma irradiation in radiosensitive tissues. Si tes of apoptosis match the tissue-specific pattern of p53 mRNA expression i ndicating that p53 regulation at mRNA level is a determinant of acute radio sensitivity of tissues. In the hematopoietic system, radiation-induced deat h 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 p otential complications of therapeutic suppression of p53 in cancer treatmen t and under other stressful conditions are discussed in relation to the p53 functions in normal development.