p53 Death Star

pressed at very low levels in normal cells. ARF expresFrom among the cast of thousands that appear to play sion can be directly activated by the transcription factors a role in the regulation of programmed cell death, p53 DMP1 and E2F1, or downregulated by factors such as has emerged as one of the leading stars. p53 is a protein Twist and Bmi1. The induction of ARF following activaof many talents, including activation of cell cycle arrest, tion of oncogenes such as Myc, Ras, and E1A may senescence, and differentiation. The special appeal of therefore, in part, reflect the activation of E2F1, and both p53, however, is as an apoptotic superhero, a protein Twist and Bmi1 can counteract this oncogene-induced that functions to selectively destroy stressed or abnorincrease in ARF expression. Now a recent study has mal cells, thereby protecting the organism from cancer identified DAP kinase, another protein with the characdevelopment. The key contribution of p53’s apoptotic teristics of a tumor suppressor, as an additional player activity to tumor suppression raises two quintessential in this pathway (Raveh et al., 2001). DAP kinase plays questions: what spurs p53 into action and how does a role in the induction of ARF and stabilization of p53 p53 implement the death sentence? Several recent pubin response to Myc and E2F1 overexpression (Figure 1) lications have thrown some interesting light on both and both Myc and E2F1 were shown to upregulate DAP issues. kinase activity. The identification of a kinase in the ARF Rules of Engagement: Regulation and Activation pathway is extremely provocative, although so far the of p53 critical targets for DAP kinase phosphorylation remain Since p53 is such a proficient inhibitor of cell growth, unknown. restraint of p53 activity during normal growth and develThe ability of mitogenic signals, such as deregulated opment is of paramount importance. p53 function is Myc, Ras, or E2F-1, to lead to the activation of p53 controlled through several mechanisms, one of the most provides an effective mechanism to prevent abnormal effective being regulation of protein stability. Central to proliferation associated with tumor development. Howthis process is MDM2, an E3 ligase that targets both ever, these fail-safe pathways pose a potentially serious p53 and itself for ubiquitination. This function of MDM2 problem to cells that want to undergo legitimate proliferhas been shown to play a role in allowing export of p53 ation. Clearly the activation of p53 needs to be dampfrom the nucleus to the cytoplasm, and degradation of ened in some way to allow normal growth, and recently p53 by the proteasome (Vousden and Vande Woude, a couple of strategies to temper the induction of p53 2000). MDM2 is a transcriptional target of p53, creating by Ras have been described. In one system, the ability a negative feedback loop where p53 activates expresof Ras to directly activate expression of MDM2 provides sion of MDM2, which keeps p53 levels low during normal a foil for the activation of ARF, which is also induced growth and development. Activation of p53 in response by Ras and inhibits MDM2 function (Ries et al., 2000) to cellular stress such as DNA damage, oncogene acti(Figure 1). Similarly JunD, which is activated by Ras, vation, telomere erosion and hypoxia is mediated, at can negatively regulate ARF expression, again counterleast in part, by inhibition of MDM2 and rapid stabilizabalancing the ability of Ras to activate ARF (Weitzman tion of the p53 protein. Depending on the activating et al., 2000). It would appear that the success of normal signal, several mechanisms to perturb MDM2 function