Cdk4/cyclin D1 kinase, a universal and critical regulator of apoptosis.

Background: We have previously described that overexpression of cdk4/cyclin Dl is the primary and critical mediator of apoptosis in PC12 cells even under otherwise physiological conditions. However, it is unclear whether this phenomenon is specific to neuronal cells or is more universally true. Materials and Methods: Cyclins and cdks were transiently overexpressed in a variety of cultured cells, and examined for apoptosis. Results: By flow cytometry, apoptosis was observed in all cell lines overexpressing cdk4 or cyclin Dl. Immunofluorescence revealed that cells overexpressing cdk4 or cyclin Dl exhibited nuclear features characteristic of apoptosis. Furthermore, in cells defective for retinoblastoma protein (Rb), apoptosis could be induced by overexpression of any cdks or cyclins. Conclusion: Up-regulation of cdk4 kinase activity is the primary and critical mediator of apoptosis regardless of the cell types. In addition, inactivation of Rb renders cells further susceptible to apoptosis by abnormal expression of any of the cell cycle regulators.