| The p53 tumor suppressor protein plays an integral role in the antiproliferative responses to many stress signals. Activation and stabilization of p53 lead to a variety of responses including cell cycle arrest and apoptosis with the choice of response dependent on factors such as cell-type, stress-type and co-activators. A crucial tumor suppression function of p53 is its ability to trigger apoptosis. Unquestionably, p53-dependent apoptosis hinges on p53's ability to serve as a transcriptional factor, modulating genes involved in apoptosis. However, p53 can promote apoptosis via transcription-independent mechanisms.; We demonstrated that induction of wild-type p53 sensitizes cells to apoptosis following exposure to several DNA-damaging agents. Many agents also induce a strong apoptotic response following expression of a transcriptionally-impaired p53 mutant, p5322/23. Moreover, apoptosis is not influenced by deletion of the last 30 amino acids of p53. Strikingly, the proline-rich domain of p53 is obligatory for induction of this cell death. Furthermore, this apoptosis can occur through two mechanisms: one dependent upon and one independent of the transactivation/repression functions of p53.; We further explored the transcription-independent functions of p53 by comparing the apoptotic features of cells expressing wild-type p53 and p53 22/23. p5322/23 apoptosis is similar to wild-type p53 apoptosis as measured by some apoptosis indicators but not others. Wild-type p53 apoptosis occurs primarily through the mitochondrial death pathway with caspases-3, -7 and -9 becoming activated. In contrast, p5322/23 apoptosis is also mitochondria-controlled but different as it occurs with delayed kinetics and without activation of the aforementioned caspases. Strikingly, both wild-type p53 and p5322/23 apoptosis implicate a significant role for caspase-2. Furthermore, caspase-2 mRNA/protein levels are down-regulated upon expression of both wild-type p53 and p5322/23.; Together, we provide evidence that the initial stage of p53-mediated apoptosis can occur by a caspase 2-dependent mechanism that not requiring the full transcriptional functions of p53. It is hypothesized that the transcription-dependent and transcription-independent functions of p53 cooperate to maximally launch an apoptotic response. |
