COOH-terminal domain of p53 modulates p53-mediated transcriptional transactivation, cell growth, and apoptosis

The tumor suppressor protein p53 contributes to the control of cell cycle c heckpoints and stress-induced apoptosis and is frequently mutated in many d ifferent types of human cancers. The COOH terminus of p53 modulates the tra nscriptional and apoptotic activities of the protein. Although COOH-termina l mutants of p53 are uncommon, we proposed that these p53 mutants neverthel ess contributed to the selective clonal expansion of the cancer cells. Ther efore, we analyzed the tumor-derived p53 COOH-terminal domain (CTD) mutants (352D/H, 356G/W, 342-stop, 360-del, and 387-del) functionally. The results have revealed that all mutants have impaired apoptotic activity when compa red with wild-type p53. However, some of these mutants still transcriptiona lly transactivate p21(Waf1/Cip1) and inhibit cell growth. Interestingly, of the tumor-derived CTD mutants, oligomerization-defective mutant 342-stop w as the only one that did not exhibit sequence-specific DNA binding or faile d to transactivate p21(Waf1/Cip1), Bar, and IGF-BP3 transcriptionally. The failure to inhibit cell growth by this tumor-derived CTD mutant supports th e hypothesis that p53 sequence-specific transcriptional transactivity to p2 1(Waf1/Cip1) is correlated with induction of cell cycle arrest and that the p53 transcriptional transactivity requires oligomerization of the p53 prot ein. These and other data indicate that the CTD of p53 is an important comp onent of p53-mediated apoptosis and cell growth arrest and that inactivatio n of the apoptotic function, but not the inhibition of growth, is an import ant step during human tumorigenesis.