Gene Silencing of Phogrin Unveils Its Essential Role in Glucose-Responsive Pancreatic β-Cell Growth

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Gene Silencing of Phogrin Unveils Its Essential Role in Glucose-Responsive Pancreatic β-Cell Growth

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dc.contributor.author Torii, Seiji
dc.contributor.author Saito, Naoya
dc.contributor.author Kawano, Ayumi
dc.contributor.author Hou, Ni
dc.contributor.author Ueki, Kohjiro
dc.contributor.author Takeuchi, Toshiyuki
dc.contributor.author Kulkarni, Rohit Narayan
dc.date.accessioned 2012-03-23T15:32:39Z
dc.date.issued 2009
dc.identifier.citation Torii, Seiji, Naoya Saito, Ayumi Kawano, Ni Hou, Kohjiro Ueki, Rohit N. Kulkarni, and Toshiyuki Takeuchi. 2009. Gene Silencing of Phogrin Unveils Its Essential Role in Glucose-Responsive Pancreatic β-Cell Growth. Diabetes 58(3): 682-692. en_US
dc.identifier.issn 0012-1797 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8438177
dc.description.abstract OBJECTIVE—Phogrin and IA-2, autoantigens in insulin-dependent diabetes, have been shown to be involved in insulin secretion in pancreatic β-cells; however, implications at a molecular level are confusing from experiment to experiment. We analyzed biological functions of phogrin in β-cells by an RNA interference technique. RESEARCH DESIGN AND METHODS—Adenovirus-mediated expression of short hairpin RNA specific for phogrin (shPhogrin) was conducted using cultured β-cell lines and mouse islets. Both glucose-stimulated insulin secretion and cell proliferation rate were determined in the phogrin-knockdown cells. Furthermore, protein expression was profiled in these cells. To see the binding partner of phogrin in β-cells, coimmunoprecipitation analysis was carried out. RESULTS—Adenoviral expression of shPhogrin efficiently decreased its endogenous expression in pancreatic β-cells. Silencing of phogrin in β-cells abrogated the glucose-mediated mitogenic effect, which was accompanied by a reduction in the level of insulin receptor substrate 2 (IRS2) protein, without any changes in insulin secretion. Phogrin formed a complex with insulin receptor at the plasma membrane, and their interaction was promoted by high-glucose stimulation that in turn led to stabilization of IRS2 protein. Corroboratively, phogrin knockdown had no additional effect on the proliferation of β-cell line derived from the insulin receptor–knockout mouse. CONCLUSIONS—Phogrin is involved in β-cell growth via regulating stability of IRS2 protein by the molecular interaction with insulin receptor. We propose that phogrin and IA-2 function as an essential regulator of autocrine insulin action in pancreatic β-cells. en_US
dc.language.iso en_US en_US
dc.publisher American Diabetes Association en_US
dc.relation.isversionof doi:10.2337/db08-0970 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646067/pdf/ en_US
dash.license LAA
dc.title Gene Silencing of Phogrin Unveils Its Essential Role in Glucose-Responsive Pancreatic β-Cell Growth en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Diabetes en_US
dash.depositing.author Kulkarni, Rohit Narayan
dc.date.available 2012-03-23T15:32:39Z
dash.affiliation.other HMS^Medicine-Brigham and Women's Hospital en_US

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