More than a decade ago, it was found that one of the two essential physiological functions of p53 is to selectively destroy stressed cells through apoptosis. Despite the large number of studies describing p53-dependent apoptosis since then, how p53 turns on the apoptotic switch has remained enigmatic. In this issue of Cancer Cell, Jeffers et al. report that knockout of PUMA, a recently identified BH3-only Bcl-2 family protein, recapitulates virtually all apoptotic deficiency in p53 knockout mice. Their results indicate that PUMA is an essential mediator of p53-dependent and -independent apoptosis in vivo.
