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Directing p53 to induce autophagy.
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MedLine Citation:
PMID:  22918242     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Comment on: Naidu SR, et al. Cell Cycle 2012; 11:2717-28.
Authors:
Lindsey D Mayo
Publication Detail:
Type:  Comment; Journal Article     Date:  2012-08-23
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-18     Completed Date:  2013-02-06     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3353-4     Citation Subset:  IM    
Affiliation:
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine; Indianapolis, IN, USA. ldmayo@iupui.edu
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MeSH Terms
Descriptor/Qualifier:
Autophagy*
Histone Acetyltransferases / metabolism*
Humans
Protein Inhibitors of Activated STAT / metabolism*
Tumor Suppressor Protein p53 / metabolism*
Chemical
Reg. No./Substance:
0/Protein Inhibitors of Activated STAT; 0/Tumor Suppressor Protein p53; EC 2.3.1.48/Histone Acetyltransferases
Comments/Corrections
Comment On:
Cell Cycle. 2012 Jul 15;11(14):2717-28   [PMID:  22751435 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Cell Cycle
Journal ID (iso-abbrev): Cell Cycle
Journal ID (publisher-id): CC
ISSN: 1538-4101
ISSN: 1551-4005
Publisher: Landes Bioscience
Article Information
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Copyright © 2012 Landes Bioscience
open-access:
Print publication date: Day: 15 Month: 9 Year: 2012
pmc-release publication date: Day: 15 Month: 9 Year: 2012
Volume: 11 Issue: 18
First Page: 3354 Last Page: 3354
PubMed Id: 22918242
ID: 3466540
Publisher Id: 2012NV0754
DOI: 10.4161/cc.21849
Publisher Item Identifier: 21849

Directing p53 to induce autophagy
Lindsey D. Mayo*
Herman B Wells Center for Pediatric Research; Indiana University School of Medicine; Indianapolis, IN USA
*Correspondence to: Lindsey D. Mayo, Email: ldmayo@iupui.edu

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.


Notes

Previously published online: www.landesbioscience.com/journals/cc/article/21849

Notes


References
1. Naidu SR,et al. Cell CycleYear: 20121127172810.4161/cc.2109122751435
2. Carter S,et al. Cell CycleYear: 2008725192810.4161/cc.7.16.642218719371
3. Tang Y,et al. Mol CellYear: 2006248273910.1016/j.molcel.2006.11.02117189186
4. Lin SY,et al. ScienceYear: 20123364778110.1126/science.121703222539723
5. Miyauchi Y,et al. J Biol ChemYear: 200227750131610.1074/jbc.M20831920012393906
6. Dohmesen C,et al. Cell CycleYear: 200872223110.4161/cc.7.2.518518264029
7. Deb SP. Mol Cancer ResYear: 20031410091614707284
8. Mancini F,et al. EMBO JYear: 20092819263910.1038/emboj.2009.15419521340

Article Categories:
  • Cell Cycle News & Views

Keywords: Keywords: PIASγ and TIP60, acetylation, autophagy, p53, sumoylation.

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