Cdk5r1 Overexpression Induces Primary β-Cell Proliferation

Journal of Diabetes Research
Carrie DraneyJeffery S Tessem

Abstract

Decreased β-cell mass is a hallmark of type 1 and type 2 diabetes. Islet transplantation as a method of diabetes therapy is hampered by the paucity of transplant ready islets. Understanding the pathways controlling islet proliferation may be used to increase functional β-cell mass through transplantation or by enhanced growth of endogenous β-cells. We have shown that the transcription factor Nkx6.1 induces β-cell proliferation by upregulating the orphan nuclear hormone receptors Nr4a1 and Nr4a3. Using expression analysis to define Nkx6.1-independent mechanisms by which Nr4a1 and Nr4a3 induce β-cell proliferation, we demonstrated that cyclin-dependent kinase 5 regulatory subunit 1 (Cdk5r1) is upregulated by Nr4a1 and Nr4a3 but not by Nkx6.1. Overexpression of Cdk5r1 is sufficient to induce primary rat β-cell proliferation while maintaining glucose stimulated insulin secretion. Overexpression of Cdk5r1 in β-cells confers protection against apoptosis induced by etoposide and thapsigargin, but not camptothecin. The Cdk5 kinase complex inhibitor roscovitine blocks islet proliferation, suggesting that Cdk5r1 mediated β-cell proliferation is a kinase dependent event. Overexpression of Cdk5r1 results in pRb phosphorylation, which is in...Continue Reading

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Citations

May 3, 2016·Journal of Autoimmunity·Diane Saunders, Alvin C Powers
Oct 17, 2018·The Biochemical Journal·Carrie DraneyJeffery S Tessem
May 26, 2016·American Journal of Physiology. Endocrinology and Metabolism·Merrick S ReynoldsJeffery S Tessem
Jul 18, 2018·Journal of Diabetes Research·Lei ZhangYanzhang Li
Oct 5, 2018·The Journal of Nutritional Biochemistry·Benjamin F BitnerAndrew P Neilson

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