The tumor suppressor p53: mechanism of action in proliferation and cell death

Normal development is a balance process, which includes proliferation and c ell death. Indeed both proliferation and apoptatic cell death are very comp lex process that involves the participation of many genes. In both events, the tumor suppressor p53 is one of the most important and studied genes. Th is transcription factor activates several genes, which results in the arres t of the cellular cycle and cellular repair or apoptosis. Many are the sign als that activate p53 function including: DNA damage by gamma or ultraviole t radiation and chemical agents and hypoxia, among others. When p53 is acti vated it can either induces the expression of p21 (Waf1, Cip-1), which part icipates in the cellular arrest between GI-S transition, or the expression of bax, PIGs, IGF-BP3, Fas, FasL and DR5. The former genes participate in t he cascade of events that induce apoptosis. Cellular arrest or apoptosis de pends of the degree of cellular damage. The final outcome of the different mechanisms of action of p53 is to maintain the genomic stability of the cel l. Thus, the absence of this protein contributes to genomic instability, th e accumulation of mutations and increased tumorigenesis. It has been demons trated that p53 present mutations in 50-55 % of all types of reported human cancer. These mutations are primary located in DNA binding domain of the p rotein, which results in the loss of its biological activity. Frequently, t umors that present wild type p53 have a better response towards therapy tha n those that present p53 mutations. This review is focused on the knowledge of the normal p53 cellular pathways and their alterations in cancer. It is clear that the understanding of p53 function in the development of this pa thology may give new insights in future therapeutic strategies including ge ne therapy for cancer.