Genes Dev 1996 Oct 1;10(19):2438-2451
Department of Biological Sciences, Columbia University, New York,
New York 10027, USA.
It is well established that induction of the p53 tumor suppressor
protein in cells can lead to either cell cycle arrest or apoptosis.
To further understand features of p53 that contribute to these cell
responses several p53-null Saos2 and H1299 cell lines were generated
that express wild-type or mutant forms of p53, or the
cyclin-dependent kinase inhibitor p21/WAF1, under a
tetracycline-regulated promoter. Our results show that the cellular
level of p53 can dictate the response of the cell such that lower
levels of p53 result in arrest whereas higher levels result in
apoptosis; nevertheless, DNA damage can heighten the apoptotic
response to p53 without altering the protein level of p53 in cells.
We also demonstrate that arrest and apoptosis are two genetically
separable functions of p53 because a transcriptionally incompetent
p53 can induce apoptosis but not arrest, whereas induction of
p21/WAF1, which is a major transcriptional target of p53, can induce
arrest but not apoptosis. Finally, we show that a full apoptotic
response to p53 requires both its amino and carboxyl terminus, and
our data suggest that there is synergism between
transcription-dependent and -independent functions of p53 in
apoptosis. Thus, there are multiple independent cellular responses to
p53 that together may account for the extraordinarily high frequency
of p53 mutations in diverse types of human tumors. The implications
of these results are discussed and a model is proposed.