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- Title
Gene silencing of phogrin unveils its essential role in glucose-responsive pancreatic beta-cell growth.
- Authors
Torii S; Saito N; Kawano A; Hou N; Ueki K; Kulkarni RN; Takeuchi T; Torii, Seiji; Saito, Naoya; Kawano, Ayumi; Hou, Ni; Ueki, Kohjiro; Kulkarni, Rohit N; Takeuchi, Toshiyuki
- Abstract
<bold>Objective: </bold>Phogrin and IA-2, autoantigens in insulin-dependent diabetes, have been shown to be involved in insulin secretion in pancreatic beta-cells; however, implications at a molecular level are confusing from experiment to experiment. We analyzed biological functions of phogrin in beta-cells by an RNA interference technique.<bold>Research Design and Methods: </bold>Adenovirus-mediated expression of short hairpin RNA specific for phogrin (shPhogrin) was conducted using cultured beta-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 beta-cells, coimmunoprecipitation analysis was carried out.<bold>Results: </bold>Adenoviral expression of shPhogrin efficiently decreased its endogenous expression in pancreatic beta-cells. Silencing of phogrin in beta-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 beta-cell line derived from the insulin receptor-knockout mouse.<bold>Conclusions: </bold>Phogrin is involved in beta-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 beta-cells.
- Publication
Diabetes, 2009, Vol 58, Issue 3, p682
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db08-0970