title: MDM2 facilitates adipocyte differentiation through CRTC-mediated activation of STAT3.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Hallenborg
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Siersbæk
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
authors.forename: I
authors.initials: I
authors.lastname: Barrio-Hernandez
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Nielsen
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen N, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
authors.forename: S
authors.identifier: 0000-0002-0961-5787
authors.initials: S
authors.lastname: Mandrup
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Grøntved
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Blagoev
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D007093:Imidazoles / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000172:deficiency / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C555318:CRTC3 protein, mouse; C497253:Cebpd protein, mouse; D002843:Chromatin; C504923:Crtc2 protein, mouse; D007093:Imidazoles; D010879:Piperazines; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051743:CCAAT-Enhancer-Binding Protein-delta; C482205:nutlin 3; D000242:Cyclic AMP; D051736:Proto-Oncogene Proteins c-mdm2; D053612:Janus Kinases