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Mol. Cell. Biol. doi:10.1128/MCB.01573-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

MafA Stability in Pancreatic -cells Is Regulated by Glucose and is Dependent on its Constitutive Phosphorylation at Multiple Sites by GSK3

Laboratory of Molecular and Developmental Biology, Graduate School of Biological Science, Nara Institute of Science and Technology, Ikoma, Japan

^* To whom correspondence should be addressed. Email: kkataoka{at}bs.naist.jp.

	Abstract

Regulation of insulin gene expression by glucose in pancreatic -cells is largely dependent on a cis-regulatory element, termed RIPE3b/C1, in the insulin gene promoter. MafA, a member of the Maf family of basic leucine-zipper (bZip) proteins, is a -cell-specific transcriptional activator that binds to the C1 element. Based on increased C1-binding activity, MafA protein levels appear to be up-regulated in response to glucose, but the underlying molecular mechanism for this is not well understood. In this study, we showed evidences supporting that the amino-terminal region of MafA is phosphorylated at multiple sites by glycogen synthase kinase 3 (GSK3) in -cells. Mutational analysis of MafA and pharmacological inhibition of GSK3 in MIN6 -cells strongly suggested that the rate of MafA protein degradation is regulated by glucose, that MafA is constitutively phosphorylated by GSK3, and that phosphorylation is a prerequisite for rapid degradation of MafA in low glucose conditions. Our data suggest a new glucose-sensing signaling pathway in islet -cells that regulates insulin gene expression through the regulation of MafA protein stability.

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