Cdk5r1 Overexpression Induces Primaryβ-Cell Proliferation

Author:

Draney Carrie1,Hobson Amanda E.1,Grover Samuel G.1,Jack Benjamin O.1,Tessem Jeffery S.1

Affiliation:

1. Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA

Abstract

Decreasedβ-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 functionalβ-cell mass through transplantation or by enhanced growth of endogenousβ-cells. We have shown that the transcription factor Nkx6.1 inducesβ-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 induceβ-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 ratβ-cell proliferation while maintaining glucose stimulated insulin secretion. Overexpression of Cdk5r1 inβ-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 mediatedβ-cell proliferation is a kinase dependent event. Overexpression of Cdk5r1 results in pRb phosphorylation, which is inhibited by roscovitine treatment. These data demonstrate that activation of the Cdk5 kinase complex is sufficient to induceβ-cell proliferation while maintaining glucose stimulated insulin secretion.

Funder

BYU Office of Research and Creative Activity

Publisher

Hindawi Limited

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism

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