title: Cdk5r1 Overexpression Induces Primary β-Cell Proliferation.
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 inhibited by roscovitine treatment. These data demonstrate that activation of the Cdk5 kinase complex is sufficient to induce β-cell proliferation while maintaining glucose stimulated insulin secretion.
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Draney
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Hobson
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Grover
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Benjamin O
authors.initials: BO
authors.lastname: Jack
authors.affiliation: Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Tessem
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D017208:Rats, Wistar; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
chemical_list: C492235:Cdk5r1 protein, rat; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; C491327:Nkx6-1 protein, rat; C539820:Nr4a1 protein, rat; C091333:Nr4a3 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D005947:Glucose