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Gene silencing of phogrin unveils its essential role in glucose-responsive pancreatic beta-cell growth.


ABSTRACT:

Objective

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.

Research design and methods

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.

Results

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.

Conclusions

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.

SUBMITTER: Torii S 

PROVIDER: S-EPMC2646067 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Gene silencing of phogrin unveils its essential role in glucose-responsive pancreatic beta-cell growth.

Torii Seiji S   Saito Naoya N   Kawano Ayumi A   Hou Ni N   Ueki Kohjiro K   Kulkarni Rohit N RN   Takeuchi Toshiyuki T  

Diabetes 20081210 3


<h4>Objective</h4>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.<h4>Research design and methods</h4>Adenovirus-mediated expression of short hairpin RNA specific for phogrin (shPhogrin) was conducted using cultured beta-cell lin  ...[more]

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