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

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 kappaB (IkappaB)-mediated inhibition of nuclear factor-kappaB 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.