MafA stability in pancreatic beta cells is regulated by glucose and is dependent on its constitutive phosphorylation at multiple sites by glycogen synthase kinase 3.
Regulation of insulin gene expression by glucose in pancreatic beta 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 beta-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 show evidence supporting that the amino-terminal region of MafA is phosphorylated at multiple sites by glycogen synthase kinase 3 (GSK3) in beta cells. Mutational analysis of MafA and pharmacological inhibition of GSK3 in MIN6 beta cells strongly suggest 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 under low-glucose conditions. Our data suggest a new glucose-sensing signaling pathway in islet beta cells that regulates insulin gene expression through the regulation of MafA protein stability.
Laboratory of Molecular and Developmental Biology, Graduate School of Biological Science, Nara Institute of Science and Technology, Ikoma, Japan.
Song-Iee
SI
Han
Shinsaku
S
Aramata
Kunio
K
Yasuda
Kohsuke
K
Kataoka
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013912:Threonine / Q000378:metabolism
D004791:Enzyme Inhibitors; D007328:Insulin; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D013912:Threonine; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose