Letter abstract
Nature Cell Biology 11, 1017 - 1023 (2009)
Published online: 13 July 2009 | doi:10.1038/ncb1915
The CDK4–pRB–E2F1 pathway controls insulin secretion
Jean-Sébastien Annicotte1,2,7, Emilie Blanchet1,2,7, Carine Chavey1,2, Irena Iankova1,2, Safia Costes3, Said Assou4, Jacques Teyssier1,2, Stéphane Dalle3, Claude Sardet5 & Lluis Fajas1,2,6
CDK4–pRB–E2F1 cell-cycle regulators are robustly expressed in non-proliferating 
cells, suggesting that besides the control of -cell number the CDK4–pRB–E2F1 pathway has a role in -cell function. We show here that E2F1 directly regulates expression of Kir6.2, which is a key component of the KATP channel involved in the regulation of glucose-induced insulin secretion. We demonstrate, through chromatin immunoprecipitation analysis from tissues, that Kir6.2 expression is regulated at the promoter level by the CDK4–pRB–E2F1 pathway. Consistently, inhibition of CDK4, or genetic inactivation of E2F1, results in decreased expression of Kir6.2, impaired insulin secretion and glucose intolerance in mice. Furthermore we show that rescue of Kir6.2 expression restores insulin secretion in E2f1-/- cells. Finally, we demonstrate that CDK4 is activated by glucose through the insulin pathway, ultimately resulting in E2F1 activation and, consequently, increased expression of Kir6.2. In summary we provide evidence that the CDK4–pRB–E2F1 regulatory pathway is involved in glucose homeostasis, defining a new link between cell proliferation and metabolism.
- INSERM, U834, Montpellier, F-34298, France.
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France. INSERM, U896, Montpellier, F-34298, France. Univ Montpellier1, Montpellier, F-34298, France; CRLC Val d'Aurelle Paul Lamarque, Montpellier, F-34298, France
- CNRS, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, F-34094, France. INSERM, U661, Equipe AVENIR, Montpellier, F-34094, France. Univ Montpellier1, 2, Montpellier, F-34094, France;
- Centre Hospitalier Universitaire, Institute for Research in Biotherapy, Hôpital Saint Eloi, Montpellier, F-34295, France.
- Institut de Génétique Moléculaire, Montpellier, F-34293, France; CNRS, UMR5535, Montpellier, F-34293, France; Univ Montpellier 2, Montpellier, F-34293, France.
- Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, F-34295, France.
- These authors contributed equally to this work.
Correspondence to: Lluis Fajas1,2,6 e-mail: lluis.fajas@inserm.fr
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