Mdm2 controls CREB-dependent transactivation and initiation of adipocyte differentiation

Abstract

The role of the E3 ubiquitin ligase murine double minute 2 (Mdm2) in regulating the stability of the p53 tumor suppressor is well documented. By contrast, relatively little is known about p53-independent activities of Mdm2 and the role of Mdm2 in cellular differentiation. Here we report a novel role for Mdm2 in the initiation of adipocyte differentiation that is independent of its ability to regulate p53. We show that Mdm2 is required for cAMP-mediated induction of CCAAT/enhancer-binding protein d (C/EBPd) expression by facilitating recruitment of the cAMP regulatory element-binding protein (CREB) coactivator, CREB-regulated transcription coactivator (Crtc2)/TORC2, to the c/ebpd promoter. Our findings reveal an unexpected role for Mdm2 in the regulation of CREB-dependent transactivation during the initiation of adipogenesis. As Mdm2 is able to promote adipogenesis in the myoblast cell line C2C12, it is conceivable that Mdm2 acts as a switch in cell fate determination.

WITHDRAWN: Gestational and lactational exposure to atrazine affects behavior and cognitive functions in Sprague-Dawley rats

“…Furthermore, this lends credit to the idea that BAI1 may not only be related to tumors, but is also an important influencing factor for functional changes in cognitive memory. Additionally, results indicated that early maternal ATR exposure induced changes in the cAMP pathway, which also altered the BAI1 pathway, all of which lends support to previous studies indicating an interconnected role of CREB, BDNF and PSD-95 [44][45][46].…”

Disruption of a regulatory loop between DUSP1 and p53 contributes to hepatocellular carcinoma development and progression

“…These results suggested that DUSP1 restoration was linked to p53 activation and expression of its target genes. Mdm2 modulates DUSP1 expression independently of p53 [24]. However, our data showed that HDM2 did not change DUSP1 expression in p53 null HCT116 p53À/À and HLK-3 cells (Supplementary Fig.…”

PPARγ neddylation essential for adipogenesis is a potential target for treating obesity

“…As a candidate for the E3 enzyme neddylating PPARγ2, we firstly considered murine double minute 2 (MDM2) because it has been known to be highly expressed in 3T3-L1 cells and to promote adipogenesis. 13,14 Ectopically expressed or endogenous MDM2 was identified to associate with PPARγ2 (Figures 4a and b). PPARγ2 neddylation by ectopic or endogenous MDM2 was verified using MDM2 siRNA and Nutlin-3 (an inhibitor of MDM2) (Figures 4c and d).…”