767 The role of p53 in the control of cell death

Abstract

The rate of growth of a cell population is dictated by the balance between proliferation on the one hand, and terminal differentiation and cell death on the other hand. Genes controlling either of these processes are likely to affect cancer development. In line with this notion, the p53 tumor suppressor gene was found to be a positive regulator of cell death. In certain cancer cells, reactivation of functional wild type (wt) p53 can trigger cell death, with distinctive features of apoptosis. Furthermore, wt p53 is required in many cases for the efficient induction of apoptosis by DNA damage or by deprivation of survival factors. We have developed an assay for the analysis of apoptosis in trans-fected HeLa cells. Using this assay, it was shown that wt p53, but not tumor-derived p53 mutants, can serve as a potent inducer of apoptosis. The pRB, the product of another tumor suppressor, can protect HeLa cells from p53-mediated apoptosis. This suggests an inverse relationship between certain growth inhibitory signals and cell death. Further experiments in the HeLa assay suggest that p53, despite being primarily a transcriptional activator, can induce apoptosis without the need to activate target genes. The relationship of these findings to the tumor suppressor effects of p53 will be discussed.