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

作　　者：Limin Han Pan Wang Ganye Zhao Hui Wang Meng Wang Jun Chen Tanjun Tong 

机构地区：[1]Peking University Research Center on Aging,Peking University Health Science Center,Beijing 100191,China [2]Department of Biochemistry&Molecular Biology,School of Basic Medicine,Peking University Health Science Center,Beijing 100191,China

出　　处：《Protein & Cell》2013年第4期310-321,共12页蛋白质与细胞（英文版）

基　　金：supported by grants from the National Basic Research Programs of China(Nos.2012CB911203 and 2013CB530801);the National Natural Science Foundation of China(Grant No.31100997);a China Postdoctoral Science Foundation funded project(No.20100470169).

摘　　要：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.

关 键 词：17Β-ESTRADIOL PPARγ senescence SIRT1 UBIQUITINATION 

分 类 号：R62[医药卫生—整形外科]