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p53 in autophagy control

Wei-Xing Zong and Ute Moll

This is an open-access article

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p53 is a well known tumor suppressor recognized for its ability to cause cell senescence and apoptosis.1 The pro-senescence function of p53 is mainly mediated by its transcriptional activation of cell cycle inhibitors. The proapoptotic function of p53 is carried out at two levels: one is through the transcriptional activation of proapoptotic proteins such as Puma, Noxa and Bax, the other is independent of its nuclear function. It physically and functionally interacts with the multi-domain members of the Bcl-2 family of proteins at mitochondria to cause mitochondrial membrane permeabilization. Stimuli such as genotoxic, hypoxic, and oncogenic stress can cause transcriptional activation as well as cytosolic accumulation with mitochondrial localization of wild-type p53 that leads to rapid mitochondrial apoptosis. Both the cytostatic and cytocidal functions of p53 contribute to its tumor suppressor nature.

Adding to its tumor suppressing activity, p53 has recently been found to also regulate autophagy.2,3 Autophagy is the process of 'self-eating' that functions to rid the cell of damaged intracellular macromolecules and organelles via degradative autophagic vacuoles, and to provide cells with energy under nutrient-starved conditions. It has been found that autophagy can be induced in a p53-dependent manner in response to genotoxins. One mechanism for p53-induced autophagy is through activation of AMPK kinase, with subsequent activation of TSC1 and TSC2 kinases, which leads to the acute inhibition of mTOR kinase (mammalian target of rapamycin), an anabolic node which controls the translation machinery and cell growth. In addition to this rapidly induced inhibition of mTOR, p53 activation also leads to upregulation of PTEN and TSC2 at the transcriptional level, which may contribute to the long-term suppression of mTOR. Another mechanism of p53-induced autophagy is through transcriptional activation of DRAM, a p53 target and a lysosomal protein. Autophagy induced by p53 may facilitate p53's cell cycle arrest activities, such that autophagy mediates the selective degradation of damaged molecules and organelles in order to provide an energy source for the damage repair process and promote 'cell healing.' Alternatively, when the extent of damage is beyond repair, autophagy may act to synergize with accelerated cell death in response to p53 activation.

Adding to these versatile functions of p53, a series of exciting recent papers from Guido Kroemer's group including two in this issue of Cell Cycle report yet another novel role of p53, namely its ability to inhibit autophagy.4,5,6 The authors find that inhibition of endogenous p53 either by genetic deletion, RNAi knockdown, or pharmacological inhibitors results in autophagy in human, mouse and nematode cells.4 They also report that in cells, several autophagy-inducing stress conditions such as nutrient starvation, ER (endoplasmic reticulum) stress, and mTOR inhibition by rapamycin all result in proteasome-mediated p53 degradation that leads to the de-repression of an autophagy program.5 Furthermore, autophagy that is induced by p53 inhibition/elimination cannot be further stimulated by ER stress, indicating that under normal (nutrient) conditions p53 maximally suppresses autophagy. The canonical nutrient sensing autophagy pathway (AMPK-mTOR-Atgs) is required for autophagy induced by p53 inhibition. Moreover, the autophagy suppression activity of p53 is strictly cell cycle-dependent, i.e., p53 inhibition triggers autophagy mostly in the G1 and less so in the S phase but never in the G2/M phase of the cycle.5 p53 degradation in response to nutrient deprivation and ER stress induces autophagy and leads to high levels of intracellular ATP. This is associated with better cell viability, and may account for cancer cell survival in the often nutrient-poor environment encountered in a 'cancer bed.' Together, these observations place p53 at the center of autophagy regulation, such that both p53 activation and suppression can lead to autophagy in response to a wide variety of cell damage signals that are either of a genotoxic or a metabolic nature, respectively.

While these observations on the p53-suppressed autophagy program might point to a role in tumor promotion, we do not yet understand its biological significance. Using retransfection of p53-/- HCT116 colon carcinoma cells with either WTp53 or a large series of p53 missense point mutants that naturally occur in human cancers, Kroemer et al find that cytoplasmic but not nuclear p53 exerts the autophagy-inhibiting function.4,6 Thus, in contrast to the autophagy-promoting activity that requires p53's nuclear transactivation activity, the autophagy-suppressing function of p53 is solely cytoplasmic and transcription-independent. Accordingly, gene expression arrays failed to identify autophagy-related genes when comparing isogenic wild-type and p53-/- HCT116 colon cancer cells. In addition, the cytoplasmic autophagy-suppressing function of p53 was found to be uncoupled from its cytoplasmic apoptosis-inducing function, since several mutants unable to interact with Bcl-2/Bcl-xL and unable to induce mitochondrial apoptosis can still inhibit autophagy. Thus, cytoplasmic p53 inhibits autophagy in a manner that is drastically distinct from both its classic transcriptional function in the nucleus and its proapoptotic function at mitochondria. And even more puzzling, the autophagy-inhibiting activity of cytoplasmic p53 does not seem to correlate with p53 tumor suppressor activity, as both tumor suppression competent and deficient, or even oncogenic, p53 mutants can inhibit autophagy, as long as they are localized in the cytoplasm.6 The coming years will likely unravel how the autophagy-suppressing function of cytoplasmic p53 is regulated, what physiologic role it plays in normal vs in nascent and established tumor cells, and how their respective status in p53 function, metabolic stress, apoptotic threshold and cell cycle progression/checkpoint influences the outcome. Finally, interesting insights can be expected once we understand the biochemical mechanism behind this novel cytoplasmic p53 function, possibly based on protein-protein interactions with autophagy regulators. Stay tuned.

References

1. Levine AJ, Hu W, Feng Z. The P53 pathway: what questions remain to be explored? Cell Death Differ 2006; 13:1027-36.
2. Jin S. p53, Autophagy and tumor suppression. Autophagy 2005; 1:171-3.
3. Crighton D, Wilkinson S, Ryan KM. DRAM links autophagy to p53 and programmed cell death. Autophagy 2007; 3:72-4.
4. Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, et al. Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 2008; 10:676-87.
5. Tasdemir E, Maiuri MC, Orhon I, Kepp O, Morselli E, Criollo A, Kroemer G. p53 represses autophagy in a cell cycle-dependent fashion. Cell Cycle 2008; In this issue.
6. Morselli E, Tasdemir E, Maiuri MC, Galluzzi L, Kepp O, Criollo A, Vicencio JM, Soussi T, Kroemer G. Mutant p53 protein localized in the cytoplasm inhibits autophagy. Cell Cycle 2008; In this issue.

Authors

Wei-Xing Zong

Stony Brook University; Stony Brook, NY

Ute Moll

Stony Brook University; Stony Brook, NY

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.