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Biochem Biophys Res Commun. 2012 Apr 6;420(2):281-7. doi: 10.1016/j.bbrc.2012.02.150. Epub 2012 Mar 6.

BMP signaling is responsible for serum-induced Id2 expression.

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Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.


Ids function as negative regulators of basic helix-loop-helix transcription factors and their expression is rapidly induced by serum stimulation in various cell types. In this study, we investigated the molecular basis of serum-induced expression of the mouse Id2 gene in NIH3T3 cells. A small-molecule inhibitor of bone morphogenetic protein (BMP) type I receptor kinases blocked the serum induction of Id2 mRNA. The chemical compound and several inhibitory proteins specific for BMP signaling suppressed the serum-induced activation of the luciferase construct with the mouse Id2 4.6-kb promoter region. Importantly, serum stimulation evoked rapid phosphorylation of Smad1/5/8 and significant activation of the reporter plasmid containing the recently identified BMP-responsive element (BRE) of the mouse Id2. Mutation analysis demonstrated that the binding sites for Smad proteins in the Id2 BRE were critical for serum response of the 4.6-kb whole construct. Gel shift and chromatin immunoprecipitation (ChIP) assays confirmed the serum-inducible binding of Smad1/5/8 and Smad4 to the Id2 BRE in vitro and in vivo. Finally, a knockdown experiment revealed the functional importance of Smad1 in the serum induction of Id2 expression. Thus, we concluded that BMP signaling is primarily responsible for the serum-induced Id2 expression. Our results also suggest that some of the cellular effects caused by serum are mediated through BMP signaling.

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