Hallenborg P, Siersbæk M, Barrio-Hernandez I, Nielsen R, Kristiansen K, Mandrup S, Grøntved L, Blagoev B
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
Department of Biology, University of Copenhagen, Copenhagen N, Denmark.
Cell Death Dis. 2016 Jun 30;7(6):e2289. doi: 10.1038/cddis.2016.188.
The ubiquitin ligase MDM2 is best known for balancing the activity of the tumor suppressor p53. We have previously shown that MDM2 is vital for adipocyte conversion through controlling Cebpd expression in a p53-independent manner. Here, we show that the proadipogenic effect of MDM2 relies on activation of the STAT family of transcription factors. Their activation was required for the cAMP-mediated induction of target genes. Interestingly, rather than influencing all cAMP-stimulated genes, inhibition of the kinases directly responsible for STAT activation, namely JAKs, or ablation of MDM2, each resulted in abolished induction of a subset of cAMP-stimulated genes, with Cebpd being among the most affected. Moreover, STATs were able to interact with the transcriptional cofactors CRTC2 and CRTC3, hitherto only reported to associate with the cAMP-responsive transcription factor CREB. Last but not least, the binding of CRTC2 to a transcriptional enhancer that interacts with the Cebpd promoter was dramatically decreased upon JAK inhibition. Our data reveal the existence of an unusual functional interplay between STATs and CREB at the onset of adipogenesis through shared CRTC cofactors.
泛素连接酶MDM2最为人所知的是它能平衡肿瘤抑制因子p53的活性。我们之前已经表明，MDM2通过以一种不依赖p53的方式控制Cebpd的表达，对脂肪细胞转化至关重要。在此，我们表明MDM2的促脂肪生成作用依赖于转录因子STAT家族的激活。它们的激活是cAMP介导的靶基因诱导所必需的。有趣的是，激酶直接负责STAT激活，即JAKs的抑制，或MDM2的缺失，并没有影响所有cAMP刺激的基因，而是导致cAMP刺激基因的一个子集的诱导被废除，Cebpd是受影响最严重的基因之一。此外，STATs能够与转录辅因子CRTC2和CRTC3相互作用，迄今为止，CRTC2和CRTC3仅报道与cAMP反应性转录因子CREB相关。最后但同样重要的是，JAK抑制后，CRTC2与一个与Cebpd启动子相互作用的转录增强子的结合显著减少。我们的数据揭示了在脂肪生成开始时，通过共享的CRTC辅因子，STATs和CREB之间存在一种不寻常的功能相互作用。
