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Cyclin D1 mediates resistance to apoptosis through upregulation of molecular chaperones and consequent redistribution of cell death regulators

Oncogene volume 27, pages 4909–4920 (2008)Cite this article

Abstract

Cyclin D1 is a key regulator of cell proliferation. It also controls other aspects of the cell fate, such as cellular senescence, apoptosis and tumourigenesis. We used B-lymphoid cell lines producing cyclin D1 to investigate the role of this protein in B-cell lymphomas and leukaemias. Constitutive low levels of cyclin D1 had no effect per se on cell proliferation, but conferred resistance to various apoptotic stimuli in B cells. Activation of the pro-apoptotic protein, Bax, was reduced and mitochondrial permeabilization and phosphatidylserine exposure following cytokine withdrawal were delayed in cyclin D1-producing cells. Proteomic analysis showed that the presence of cyclin D1 led to intracellular accumulation of various molecular chaperones. The chaperone, heat shock protein (Hsp)70, bound to both Bax and the mitochondrial apoptosis inducing factor following cytokine withdrawal, and impeded inhibitors of κB (IκB)-mediated inhibition of nuclear factor-κB anti-apoptotic signalling. Impairment of Hsp70 activity—using a pharmacological Hsp inhibitor or transfecting cells with an Hsp70-blocking antibody—restored the cellular response to mitochondrial apoptosis triggering. Thus, constitutive de-novo cyclin D1 production in B cells delays commitment to apoptosis by inducing Hsp70 chaperoning activity on pre- and post-mitochondrial pro-apoptotic factors.

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Acknowledgements

We thank A Barbaras and S Cabezas for expert technical assistance and JM Renoir (CNRS UMR 8612, Université de Paris Sud, France) for the gift of anti-Hsp70/90 antibody. The work was financially supported by the Ligue contre le Cancer—Comité du Calvados, Cent pour sang la vie and the Association pour la Recherche contre le Cancer (grant nos. 7791 and 3426) to BS, and by the Spanish Ministry of Education and Science (grant SAF06/8850) to DC. GR received a scholarship from the Ligue Nationale contre le Cancer—Comité du Calvados and has a postdoctoral position with the C-RED programme (Generalitat de Catalunya, Spain).

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Authors and Affiliations

  1. Biologie moléculaire et cellulaire de la signalisation—EA 3919, IFR 146, Université de Caen, Caen, France

    G Roué & B Sola

  2. Unitat d'Hematopatologia, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain

    G Roué & D Colomer

  3. Laboratoire de Microbiologie de l'Environnement—USC INRA 2017—EA 956, IFR 146, Université de Caen, Caen, France

    V Pichereau

  4. GRECAN—EA1773, IFR 146, Centre de lutte contre le cancer François Baclesse, Caen, France

    H Lincet

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Correspondence to G Roué.

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Roué, G., Pichereau, V., Lincet, H. et al. Cyclin D1 mediates resistance to apoptosis through upregulation of molecular chaperones and consequent redistribution of cell death regulators. Oncogene 27, 4909–4920 (2008). https://doi.org/10.1038/onc.2008.126

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