Directing p53 to induce autophagy.

Macroautophagy is an ancient, evolutionarily conserved catabolic process involving the degradation of organelles and long-lived proteins, an important process for maintaining cellular homeostasis. Many cellular stresses, including hypoxia/anoxia and the lack of growth factors and nutrients, trigger autophagy to either mediate survival or cell death. Numerous intracellular factors have been implicated in promoting autophagy, including the tumor suppressor p53. Interestingly, p53 can promote cell fate decisions such as autophagy through transcriptional and post-transcriptional pathways. The complexity of how p53 can regulate cellular fate may be driven by specific pathways that are activated in response to cellular cues, while the understanding of intra- and extracellular signaling that promotes post-translational modifications to p53 still remains incomplete. For example, various enzymes lead to phosphorylation, acetylation, glycosylation, ubiqutination, neddylation, sumoylation and methylation of p53, which are implicated in regulating the activity of p53. These specific posttranslational modifications would most likely change the recruitment of specific proteins, DNA binding or changes in compartmentalization of p53. The combination of specific modifications that are necessary to fine-tune p53 activity are still not well-defined. The signaling pathways that would activate specific enzymes to direct p53 to mediate cellular processes such as autophagy is important to understand, since manipulating these enzymes pharmacologically would be of therapeutic value. A recent paper by Naidu, et al. examines how post-translational modifications to p53 direct its activity to promote autophagy.1 Since post-translational modifications to p53 in the C terminus (ubiquitin and sumoylation) have been implicated in redistribution of p53 to the cytoplasm,2 the authors rationalized that post-transcriptional activity of p53 in the cytoplasm would be a key event in regulating autophagy. They show that in order for p53 to mediate autophagy sumoylation at K386 and acetylation of lysine 120 are necessary for facilitating the conversion of LC3, a key protein involved in autophagy. TIP60 can acetylate p53 at lysine 120, which is necessary for induction of the p21 gene and the pro-apoptotic gene, puma.3 Recent work by Lin, et al. showed that TIP60 was necessary for the induction of autophagy,4 which is also reported by Naidu, et al. herein.1 Collectively, Naidu, et al.’s studies show that PIASγ can modify and activate TIP60, resulting in TIP60 and PIASγ post-translational modifications to p53 that redirects its activity to induce autophagy In light of these new findings, some additional biochemical questions remain, including how the regulator of p53, Mdm2, is involved in this pathway. Interestingly, Mdm2 forms a complex with, and is acetylated and sumoylated, by TIP60 and PIASγ, respectively.5,6 Both modifications independently inactivate the ubiquitin ligase activity of Mdm2. Since TIP60/PIASγ regulate p53 and TIP60/PIASγ can regulate Mdm2, this suggests that Mdm2 may be serving as a scaffold to mediate these modifications to p53. It would be interesting to determine if Mdm2 can facilitate these modifications, as Mdm2 has been reported to have cellular-suppressor activity.7 Additionally, considering that the Mdm2 family member Mdmx is found with p53 in the cytoplasm,8 Mdmx may also be playing a role in regulating p53-mediated autophagy. Further work is also needed to establish a biochemical understanding of the events necessary to direct p53 for induction of autophagy and if preventing the p53-Mdm2 or p53-Mdmx complex using small-molecule inhibitors would promote or halt the induction of autophagy.