title: Serum response factor expression is enriched in pancreatic β cells and regulates insulin gene expression.
abstract: Serum response factor (SRF) is an essential regulator of myogenic and neurogenic genes and the ubiquitously expressed immediate-early genes. The purpose of this study is to determine SRF expression pattern in murine pancreas and examine the role of SRF in pancreatic gene expression. Immunohistochemical analysis of wild-type pancreas and LacZ staining of pancreas from SRF LacZ knock-in animals showed that SRF expression is restricted to β cells. SRF bound to the rat insulin promoter II (RIP II) serum response element, an element conserved in both rat I and murine I and II insulin promoters. SRF activated RIP II, and SRF binding to RIP II and the exon 5-encoded 64-aa subdomain of SRF was required for this activation. Transient or stable knockdown of SRF leads to down-regulation of insulin gene expression, suggesting that SRF is required for insulin gene expression. Further, SRF physically interacted with the pancreas and duodenum homeobox-1 (Pdx-1) and synergistically activated RIP II. Elevated glucose concentration down-regulated SRF binding to RIP II SRE, and this down-regulation was associated with decreased RIP II activity and increased SRF phosphorylation on serine 103. Together, our results demonstrate that SRF is a glucose concentration-sensitive regulator of insulin gene expression.
authors.affiliation: Michael E. DeBakey VA Medical Center, 2002 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Aloke
authors.initials: A
authors.lastname: Sarkar
authors.forename: Mao
authors.initials: M
authors.lastname: Zhang
authors.forename: Shi-He
authors.initials: SH
authors.lastname: Liu
authors.forename: Swapna
authors.initials: S
authors.lastname: Sarkar
authors.forename: F Charles
authors.initials: FC
authors.lastname: Brunicardi
authors.forename: David H
authors.initials: DH
authors.lastname: Berger
authors.forename: Narasimhaswamy S
authors.initials: NS
authors.lastname: Belaguli
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D026362:Serum Response Factor / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D034741:RNA, Small Interfering; D026362:Serum Response Factor; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose