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. 2013 Apr 3;4(4):310–321. doi: 10.1007/s13238-013-2124-z

Upregulation of SIRT1 by 17β-estradiol depends on ubiquitin-proteasome degradation of PPAR-γ mediated by NEDD4-1

Limin Han 12124,22124, Pan Wang 12124,22124, Ganye Zhao 12124,22124, Hui Wang 12124,22124, Meng Wang 12124,22124, Jun Chen 12124,22124,✉, Tanjun Tong 12124,22124,✉
PMCID: PMC4703587  PMID: 23549616

Abstract

17β-estradiol (E2) treatment of cells results in an upregulation of SIRT1 and a down-regulation of PPARγ. The decrease in PPARγ expression is mediated by increased degradation of PPARγ. Here we report that PPARγ is ubiquitinated by HECT E3 ubiquitin ligase NEDD4-1 and degraded, along with PPARγ, in response to E2 stimulation. The PPARγ interacts with ubiquitin ligase NEDD4-1 through a conserved PPXY-WW binding motif. The WW3 domain in NEDD4-1 is critical for binding to PPARΓ. NEDD4-1 overexpression leads to PPARγ ubiquitination and reduced expression of PPARγ. Conversely, knockdown of NEDD4-1 by specific siRNAs abolishes PPARΓ ubiquitination. These data indicate that NEDD4-1 is the E3 ubiquitin ligase responsible for PPARγ ubiquitination. Here, we show that NEDD4-1 delays cellular senescence by degrading PPARΓ expression. Taken together, our data show that E2 could upregulate SIRT1 expression via promoting the PPARΓ ubiquitination-proteasome degradation pathway to delay the process of cell senescence.

Keywords: 17β-estradiol, PPARγ, senescence, SIRT1, ubiquitination

Footnotes

These authors contributed equally to the work.

Contributor Information

Jun Chen, Email: chenjun0511@yahoo.com.

Tanjun Tong, Email: ttj@bjmu.edu.cn.

References

  1. Adams M, Reginato MJ, Shao D, Lazar MA, Chatterjee VK. Transcriptional activation by peroxisome proliferators-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J Biol Chem. 1997;272:5128–5132. doi: 10.1074/jbc.272.8.5128. [DOI] [PubMed] [Google Scholar]
  2. Bake S, Sohrabji F. 17 beta-estradiol differentially regulates blood-brain barrier permeability in young and aging female rats. Endocrinology. 2004;145:5471–5475. doi: 10.1210/en.2004-0984. [DOI] [PubMed] [Google Scholar]
  3. Blanquart C, Barbier O, Fruchart JC, Staels B, Glineur C. Peroxisome proliferator-activated receptor alpha (PPARalpha) turnover by the ubiquitin-proteasome system controls the ligand-induced expression level of its target genes. J Biol Chem. 2002;277:37254–37259. doi: 10.1074/jbc.M110598200. [DOI] [PubMed] [Google Scholar]
  4. Boudjelal M, Wang Z, Voorhees JJ, Fisher GJ. Ubiquitin/proteasome pathway regulates levels of retinoic acid receptor gamma and retinoid X receptor alpha in human keratinocytes. Cancer Res. 2000;60:2247–2252. [PubMed] [Google Scholar]
  5. Camp HS, Tafuri SR. Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase. J Biol Chem. 1997;272:10811–10816. doi: 10.1074/jbc.272.16.10811. [DOI] [PubMed] [Google Scholar]
  6. Camp HS, Tafuri SR, Leff T. c-Jun N-terminal kinase phosphorylates peroxisome proliferator-activated receptor-gamma1 and negatively regulates its transcriptional activity. Endocrinology. 1999;140:392–397. doi: 10.1210/endo.140.1.6457. [DOI] [PubMed] [Google Scholar]
  7. Chang TH, Szabo E. Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in non-small cell lung cancer. Cancer Res. 2000;60:1129–1138. [PubMed] [Google Scholar]
  8. Dace A, Zhao L, Park KS, Furuno T, Takamura N, Nakanishi M, West BL, Hanover JA, Cheng S. Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors. Proc Natl Acad Sci U S A. 2000;97:8985–8990. doi: 10.1073/pnas.160257997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995;92:9363–9367. doi: 10.1073/pnas.92.20.9363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Floyd ZE, Stephens JM. Interferon-gamma-mediated activation and ubiquitin-proteasome-dependent degradation of PPAR gamma in adipocytes. Journal of Biological Chemistry. 2002;277:4062–4068. doi: 10.1074/jbc.M108473200. [DOI] [PubMed] [Google Scholar]
  11. Gan Q, Huang J, Zhou R, Niu J, Zhu X, Wang J, Zhang Z, Tong T. PPAR{gamma} accelerates cellular senescence by inducing p16INK4{alpha} expression in human diploid fibroblasts. J Cell Sci. 2008;121:2235–2245. doi: 10.1242/jcs.026633. [DOI] [PubMed] [Google Scholar]
  12. Han L, Zhou R, Niu J, McNutt MA, Wang P, Tong T. SIRT1 is regulated by a PPAR{Γ}-SIRT1 negative feedback loop associated with senescence. Nucleic Acids Res. 2010;38:7458–7471. doi: 10.1093/nar/gkq609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Huser S, Adelmant G, Sarraf P, Wright HM, Mueller E, Spiegelman BM. Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. J Biol Chem. 2000;275:18527–18533. doi: 10.1074/jbc.M001297200. [DOI] [PubMed] [Google Scholar]
  14. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–479. doi: 10.1146/annurev.biochem.67.1.425. [DOI] [PubMed] [Google Scholar]
  15. Hodges M, Tissot C, Freemont PS. Protein regulation: tag wrestling with relatives of ubiquitin. Curr Biol. 1998;8:R749–752. doi: 10.1016/S0960-9822(07)00477-0. [DOI] [PubMed] [Google Scholar]
  16. Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science. 1996;274:2100–2103. doi: 10.1126/science.274.5295.2100. [DOI] [PubMed] [Google Scholar]
  17. Ingham RJ, Gish G, Pawson T. The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture. Oncogene. 2004;23:1972–1984. doi: 10.1038/sj.onc.1207436. [DOI] [PubMed] [Google Scholar]
  18. Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes & Dev. 1999;13:2570–2580. doi: 10.1101/gad.13.19.2570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kelly D, Campbell JI, King TP, Grant G, Jansson EA, Coutts AG, Pettersson S, Conway S. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol. 2004;5:104–112. doi: 10.1038/ni1018. [DOI] [PubMed] [Google Scholar]
  20. Kopf E, Plassat JL, Vivat V, de The H, Chambon P, Rochette-Egly C. Dimerization with retinoid X receptors and phosphorylation modulate the retinoic acid-induced degradation of retinoic acid receptors alpha and gamma through the ubiquitinproteasome pathway. J Biol Chem. 2000;275:33280–33288. doi: 10.1074/jbc.M002840200. [DOI] [PubMed] [Google Scholar]
  21. Lazennec G, Canaple L, Saugy D, Wahli W. Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators. Mol Endocrinol. 2000;14:1962–1975. doi: 10.1210/mend.14.12.0575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Limin Han RZ, Jing Niu, Michael A, McNutt, Pan W, Tanjun T. SIRT1 is regulated by a PPAR-Γ -SIRT1 negative feedback loop associated with senescence. Nucleic Acids Research. 2010;38:21. doi: 10.1093/nar/gkp1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Majumder PK, Grisanzio C, O’Connell F, Barry M, Brito JM, Xu Q, Guney I, Berger R, Herman P, Bikoff R, et al. A prostatic intraepithelial neoplasia-dependent p27Kip1checkpoint induces senescence and inhibits cell proliferation and cancer progression. Cancer Cell. 2008;14:146–155. doi: 10.1016/j.ccr.2008.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Masoro EJ. Caloric restriction and aging: an update. Exp Gerontol. 2000;35:299–305. doi: 10.1016/S0531-5565(00)00084-X. [DOI] [PubMed] [Google Scholar]
  25. Mimnaugh EG, Bonvini P, Neckers L. The measurement of ubiquitin and ubiquitinated proteins. Electrophoresis. 1999;20:418–428. doi: 10.1002/(SICI)1522-2683(19990201)20:2<418::AID-ELPS418>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  26. Muratani M, Tansey WP. How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol. 2003;4:192–201. doi: 10.1038/nrm1049. [DOI] [PubMed] [Google Scholar]
  27. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004;429:771–776. doi: 10.1038/nature02583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev. 2000;14:1293–1307. [PubMed] [Google Scholar]
  29. Rotin D, Staub O, Haguenauer-Tsapis R. Ubiquitination and endocytosis of plasma membrane proteins: role of Nedd4/Rsp5p family of ubiquitin-protein ligases. J Membr Biol. 2000;176:1–17. doi: 10.1007/s00232001079. [DOI] [PubMed] [Google Scholar]
  30. Sudol M, Hunter T. NeW wrinkles for an old domain. Cell. 2000;103:1001–1004. doi: 10.1016/S0092-8674(00)00203-8. [DOI] [PubMed] [Google Scholar]
  31. Wang XJ, Trotman LC, Koppie T, Alimonti A, Chen ZB, Gao ZH, Wang JR, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, et al. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell. 2007;128:129–139. doi: 10.1016/j.cell.2006.11.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Weissman AM. Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol. 2001;2:169–178. doi: 10.1038/35056563. [DOI] [PubMed] [Google Scholar]
  33. Zhang B, Berger J, Zhou G, Elbrecht A, Biswas S, White-Carrington S, Szalkowski D, Moller DE. Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor gamma. J Biol Chem. 1996;271:31771–31774. doi: 10.1074/jbc.271.50.31771. [DOI] [PubMed] [Google Scholar]
  34. Zhang H, Cohen SN. Smurf2 up-regulation activates telomere-dependent senescence. Genes Dev. 2004;18:3028–3040. doi: 10.1101/gad.1253004. [DOI] [PMC free article] [PubMed] [Google Scholar]

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