Cycling to Cancer with Cyclin D1

AbstractGenetic aberrations in the regulatory circuits that govern transit through the G1 phase of the cell cycle occur frequently in human cancer and overexpression of the G1 phase cyclin, cyclin D1, is one of the most commonly observed alterations. Cyclin D1 accumulates and activates its cognate CDK (CDK4/6) in response to mitogenic growth factors in early to mid G1 phase. The resulting cyclin D1-dependent kinase initiates the phosphorylation-dependent inactivation of the retinoblastoma tumor suppressor protein. Mitogen-dependent activation of the cyclin D1 kinase occurs through increased transcription, protein accumulation, cyclin/CDK assembly, reduced cyclin proteolysis, and decreased nuclear export. Perturbations at any step, which result in reduced growth factor requirements for cyclin D1/CDK activation, will provide cells with a distinct growth advantage over their normal counterparts and thus likely represents an early event in neoplasia.