Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein α
| Autor: | Sven Wang, Rui Chang, Ellen S.T. Yang, Randy Strich, Yi Zhang, Quanwei Zhang, Jeffrey E. Pessin, Alus M. Xiaoli, Fajun Yang, Ziyi Song, Zhengdong Zhang, Gongshe Yang |
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| Rok vydání: | 2017 |
| Předmět: |
Transcriptional Activation
0301 basic medicine Cellular differentiation Peroxisome proliferator-activated receptor Biology Biochemistry Mice 03 medical and health sciences Transactivation chemistry.chemical_compound Cyclin C 3T3-L1 Cells Adipocyte Gene expression Animals Humans Molecular Biology Mice Knockout chemistry.chemical_classification Regulation of gene expression Adipogenesis Ccaat-enhancer-binding proteins Cell Differentiation Cell Biology Cell biology PPAR gamma Adipocytes Brown Metabolism 030104 developmental biology chemistry CCAAT-Enhancer-Binding Proteins |
| Zdroj: | Journal of Biological Chemistry. 292:8918-8932 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m117.776229 |
| Popis: | Brown adipose tissue is important for maintaining energy homeostasis and adaptive thermogenesis in rodents and humans. As disorders arising from dysregulated energy metabolism, such as obesity and metabolic diseases, have increased, so has interest in the molecular mechanisms of adipocyte biology. Using a functional screen, we identified cyclin C (CycC), a conserved subunit of the Mediator complex, as a novel regulator for brown adipocyte formation. siRNA-mediated CycC knockdown (KD) in brown preadipocytes impaired the early transcriptional program of differentiation, and genetic KO of CycC completely blocked the differentiation process. RNA sequencing analyses of CycC-KD revealed a critical role of CycC in activating genes co-regulated by peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Overexpression of PPARγ2 or addition of the PPARγ ligand rosiglitazone rescued the defects in CycC-KO brown preadipocytes and efficiently activated the PPARγ-responsive promoters in both WT and CycC-KO cells, suggesting that CycC is not essential for PPARγ transcriptional activity. In contrast, CycC-KO significantly reduced C/EBPα-dependent gene expression. Unlike for PPARγ, overexpression of C/EBPα could not induce C/EBPα target gene expression in CycC-KO cells or rescue the CycC-KO defects in brown adipogenesis, suggesting that CycC is essential for C/EBPα-mediated gene activation. CycC physically interacted with C/EBPα, and this interaction was required for C/EBPα transactivation domain activity. Consistent with the role of C/EBPα in white adipogenesis, CycC-KD also inhibited differentiation of 3T3-L1 cells into white adipocytes. Together, these data indicate that CycC activates adipogenesis in part by stimulating the transcriptional activity of C/EBPα. |
| Databáze: | OpenAIRE |
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