Unleashing the power of p53: lessons from mice and men

It is well established that many forms of cellular stress activate the tumor suppressor p53 with ensuing cellular outcomes such as arrest, senescence, or death (Prives and Hall 1999; Vousden and Lu 2002). Although not yet fully understood, each of these is likely in some contexts to be required for p53 to suppress tumorigenesis (Vousden and Prives 2005). It follows that in the absence of such stress signals, there is also a requirement to keep p53 under tight control until needed. It is now clear that this is largely accomplished by its negative regulator, Mdm2, an E3 ubiquitin ligase that binds to p53 and can both prevent p53 from functioning effectively as a transcriptional activator and target it for proteasomal degradation (Iwakuma and Lozano 2003). Mdm2 works with another homologous protein, MdmX, that can also down-regulate the transcription function of but cannot degrade p53 (Marine and Jochemsen 2005). There are now several published experiments supporting the importance of maintaining the p53-Mdm2-MdmX circuitry, perhaps the most compelling being the fact that it is not possible to produce viable Mdm2- or Mdmx-null mice unless either are generated in a p53-null background (Jones et al. 1995; Montes de Oca Luna et al. 1995; Parant et al. 2001; Migliorini et al. 2002). Understanding the relationship between these genes is not merely an academic question (even though as such it is a fascinating one); about half of all human tumors express wild-type p53, and a significant proportion of these cancers overexpress Mdm2 (Momand et al. 2000). Therefore, finding ways to prevent down-regulation of p53 by Mdm2 in tumors without affecting normal cells is a highly sought therapeutic goal. Recent studies in mice and human patients including one in the previous issue (Mendrysa et al. 2006) of Genes & Development have brought …