title: Cyclin C stimulates β-cell proliferation in rat and human pancreatic β-cells.
abstract: Activation of pancreatic β-cell proliferation has been proposed as an approach to replace reduced functional β-cell mass in diabetes. Quiescent fibroblasts exit from G0 (quiescence) to G1 through pRb phosphorylation mediated by cyclin C/cdk3 complexes. Overexpression of cyclin D1, D2, D3, or cyclin E induces pancreatic β-cell proliferation. We hypothesized that cyclin C overexpression would induce β-cell proliferation through G0 exit, thus being a potential therapeutic target to recover functional β-cell mass. We used isolated rat and human islets transduced with adenovirus expressing cyclin C. We measured multiple markers of proliferation: [(3)H]thymidine incorporation, BrdU incorporation and staining, and Ki67 staining. Furthermore, we detected β-cell death by TUNEL, β-cell differentiation by RT-PCR, and β-cell function by glucose-stimulated insulin secretion. Interestingly, we have found that cyclin C increases rat and human β-cell proliferation. This augmented proliferation did not induce β-cell death, dedifferentiation, or dysfunction in rat or human islets. Our results indicate that cyclin C is a potential target for inducing β-cell regeneration.
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan;
authors.forename: Margarita
authors.initials: M
authors.lastname: Jiménez-Palomares
authors.affiliation: Instituto de Genética y Biología Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain;
authors.forename: José Francisco
authors.initials: JF
authors.lastname: López-Acosta
authors.affiliation: Instituto de Genética y Biología Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain;
authors.forename: Pablo
authors.initials: P
authors.lastname: Villa-Pérez
authors.affiliation: Pancreatic Islet Isolation Unit, IDIBELL-Hospital Duran i Reynals, Barcelona, Spain; and.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Moreno-Amador
authors.affiliation: Instituto de Genética y Biología Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Muñoz-Barrera
authors.affiliation: Instituto de Genética y Biología Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain;
authors.forename: Sara
authors.initials: S
authors.lastname: Fernández-Luis
authors.affiliation: Instituto de Genética y Biología Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain;
authors.forename: Blanca
authors.initials: B
authors.lastname: Heras-Pozas
authors.affiliation: Departamento de Química Inorgánica, Orgánica y Bioquímica, Universidad de Castilla La Mancha, Spain.
authors.forename: Germán
authors.initials: G
authors.lastname: Perdomo
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan;
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
authors.affiliation: Instituto de Genética y Biología Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain; irene.cozar@ibgm.uva.es.
authors.forename: Irene
authors.initials: I
authors.lastname: Cózar-Castellano
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D056745:Cyclin C / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051381:Rats; D017208:Rats, Wistar
chemical_list: D056745:Cyclin C
keywords: cell cycle; cyclin C; pancreatic β-cell; proliferation