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MDM2 facilitates adipocyte differentiation through CRTC-mediated activation of STAT3

P Hallenborg1, M Siersbæk1, I Barrio-Hernandez1

  • 1Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.

Cell Death & Disease
|July 1, 2016
PubMed

Insights

The ubiquitin ligase MDM2 promotes adipocyte differentiation by activating STAT transcription factors. This process involves STATs interacting with CRTC cofactors, crucial for regulating Cebpd gene expression during fat cell development.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The ubiquitin ligase MDM2 regulates the tumor suppressor p53.
  • MDM2 is essential for adipocyte differentiation, acting independently of p53.
  • MDM2 controls Cebpd expression, a key gene in adipogenesis.

Purpose of the Study:

  • To elucidate the mechanism by which MDM2 promotes adipogenesis.
  • To investigate the role of STAT transcription factors in MDM2-mediated adipocyte differentiation.
  • To explore the interaction between MDM2, STATs, and CREB signaling pathways.

Main Methods:

  • Investigated MDM2's role in adipocyte conversion.
  • Analyzed STAT family transcription factor activation.
  • Utilized JAK inhibition and MDM2 ablation studies.
  • Examined interactions between STATs, CRTC2/3, and CREB.
  • Assessed CRTC2 binding to the Cebpd transcriptional enhancer.

Main Results:

  • MDM2's proadipogenic effect depends on STAT activation.
  • STAT activation is necessary for cAMP-mediated gene induction.
  • Inhibition of JAKs or ablation of MDM2 selectively abolished induction of a subset of cAMP-stimulated genes, including Cebpd.
  • STATs interact with CRTC2 and CRTC3, cofactors typically associated with CREB.
  • JAK inhibition significantly reduced CRTC2 binding to a Cebpd enhancer.

Conclusions:

  • MDM2 activates STATs, which are crucial for adipogenesis.
  • A novel interplay exists between STATs and CREB signaling via shared CRTC cofactors during adipogenesis.
  • This study reveals a new regulatory mechanism for adipocyte differentiation involving MDM2, STATs, and CRTCs.

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