Background: Cyclin D1 and its kinase partners control cell cycle progression. Cyclin D1 is frequently deregulated in\nvarious cancers, including malignant hemopathies, and tumor cells display uncontrolled cell proliferation. Cyclin D1\nis not expressed in the B-cell lineage but is found in multiple myeloma (MM) cells in almost 50% of patients with\nthis condition. Paradoxically, cyclin D1 expression is associated with a good prognosis and longer overall survival in\nMM patients.\nMethods: We used two independent MM cell lines (RPMI 8226 and LP1) to generate several clones stably expressing\neither the green fluorescent protein (GFP) or a GFP-cyclin D1 fusion protein, and we analyzed the properties acquired\nfollowing cyclin D1 expression.\nResults: Whole-genome expression analysis in the cell clones indicated that cyclin D1 profoundly modified several\ncellular functions, including the regulation of apoptotic cell death. We studied the apoptotic response of GFP- and\nGFP-cyclin D1-expressing clones to bortezomib-treatment. We found that the apoptotic response occurred faster\nand was of a greater amplitude in cyclin D1-expressing cells. Cyclin D1 expression enhanced the caspase-dependent\napoptosis mediated by the intrinsic mitochondrial pathway. More importantly, cyclin D1 also activated the unfolded\nprotein response (UPR) and induced endoplasmic reticulum (ER) stress-mediated apoptosis.\nConclusion: The ER is well known to be a crucial regulator of plasma cell death and it plays the same role in their\nmalignant counterparts, myeloma cells. This role involves activation of the UPR controlled at least in part by cyclin D1
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