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Cell Death Dis. 2016 Jun 30;7(6):e2289. doi: 10.1038/cddis.2016.188.

MDM2 facilitates adipocyte differentiation through CRTC-mediated activation of STAT3.

Author information

1
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
2
Department of Biology, University of Copenhagen, Copenhagen N, Denmark.

Abstract

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.

PMID:
27362806
PMCID:
PMC5108339
DOI:
10.1038/cddis.2016.188
[Indexed for MEDLINE]
Free PMC Article

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