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The CDK4–pRB–E2F1 pathway controls insulin secretion

Nature Cell Biology volume 11, pages 1017–1023 (2009)Cite this article

Abstract

CDK4–pRB–E2F1 cell-cycle regulators are robustly expressed in non-proliferating β cells, suggesting that besides the control of β-cell number the CDK4–pRB–E2F1 pathway has a role in β-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−/− β 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.

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Figure 1: Decreased secretagogue-stimulated insulin secretion in E2f1−/− mice.
Figure 2: Kir6.2, a component of the KATP channels that regulates insulin secretion, is a direct E2F1 target gene.
Figure 3: Glucose regulates CDK4 activity, pRB phosphorylation and E2F1 transcriptional activity both in vitro and in vivo.
Figure 4: Insulin regulates CDK4 activity, pRB phosphorylation and E2F1 transcriptional activity in vivo through an autocrine effect.
Figure 5: Glucose intolerance, decreased insulin secretion and KIR6.2 levels in C57Bl/6 treated with CDK4 inhibitor.

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Acknowledgements

We thank K.H. Kaestner (pGL3–Kir6.2–Luc), S. Seino and Y. Kurachi (pCDNA3–Kir6.2) for the gift of materials; I. Ait Arssa, M. Brissac, C. Clapé, D. Greuet, C. Henriquet and S. Hure for excellent technical help; L. Le Cam. Members of the Fajas lab are acknowledged for support and discussions. This work was supported by grants from Agence Nationale pour la Recherche (ANR physio2006), INSERM-Association Française des Diabétiques (PNR-Diabète), Association pour la Recherche contre le Cancer, and Fondation pour la Recherche Médicale. E.B. is supported by a grant form the Ministère de l'Enseignement Supérieur et de la Recherche, C.C. is supported by a grant from the Agence Nationale pour la Recherche.

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Author notes

  1. Jean-Sébastien Annicotte and Emilie Blanchet: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, U834, Montpellier, F-34298, France

    Jean-Sébastien Annicotte, Emilie Blanchet, Carine Chavey, Irena Iankova, Jacques Teyssier & Lluis Fajas

  2. 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,

    Jean-Sébastien Annicotte, Emilie Blanchet, Carine Chavey, Irena Iankova, Jacques Teyssier & Lluis Fajas

  3. CRLC Val d'Aurelle Paul Lamarque, Montpellier, F-34298, France,

    Jean-Sébastien Annicotte, Emilie Blanchet, Carine Chavey, Irena Iankova & Jacques Teyssier

  4. 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

    Safia Costes & Stéphane Dalle

  5. Centre Hospitalier Universitaire, Institute for Research in Biotherapy, Hôpital Saint Eloi, Montpellier, F-34295, France

    Said Assou

  6. Institut de Génétique Moléculaire, Montpellier, F-34293, France

    Claude Sardet

  7. CNRS, UMR5535, Montpellier, F-34293, France

    Claude Sardet

  8. Univ Montpellier 2, Montpellier, F-34293, France

    Claude Sardet

  9. Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, F-34295, France

    Lluis Fajas

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  1. Jean-Sébastien Annicotte
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Contributions

J-S. A. and L.F designed the study; J-S. A., E.B., C.C., I.I., S.C., S.A. and J.T performed the experiments; S.D. and C.S. provided reagents and data; J-S. A. and L.F wrote the manuscript.

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Correspondence to Lluis Fajas.

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Annicotte, JS., Blanchet, E., Chavey, C. et al. The CDK4–pRB–E2F1 pathway controls insulin secretion. Nat Cell Biol 11, 1017–1023 (2009). https://doi.org/10.1038/ncb1915

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