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
| Title: | Gene Silencing of Phogrin Unveils Its Essential Role in Glucose-Responsive Pancreatic β-Cell Growth |
| Author: |
Torii, Seiji; Saito, Naoya; Kawano, Ayumi; Hou, Ni; Ueki, Kohjiro; Takeuchi, Toshiyuki; Kulkarni, Rohit Narayan
Note: Order does not necessarily reflect citation order of authors. |
| 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. |
| Full Text & Related Files: |
2646067.pdf (1.037Mb; PDF) 
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| 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. |
| Published Version: | doi:10.2337/db08-0970 |
| Other Sources: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646067/pdf/ |
| Terms of Use: | This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA |
| Citable link to this page: | http://nrs.harvard.edu/urn-3:HUL.InstRepos:8438177 |
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