Sequence-specific transcriptional activation is essential for growth suppression by p53

Although several biochemical features of p53 have been described, their relationship to tumor suppression remains uncertain. We have compared the ability of p53-derived proteins to act as sequence-specific transcriptional (SST) activators with their ability to suppress tumor cell growth, using an improved growth-suppression assay. Both naturally occurring and in vitro derived mutations that abrogated the SST activity of p53 lost the ability to suppress tumor cell growth. Additionally, the N- and C-terminal ends of p53 were shown to be functionally replaceable with foreign transactivation and dimerization domains, respectively, with concordant preservation of both SST and tumor-suppressive properties. Only the central region of p53, conferring specific DNA binding, was required to suppress growth by such hybrid proteins. The SST activity of p53 thus appeared to be essential for the protein to function as a tumor suppressor.