Perturbation of cell cycle regulators in human cancer.

Progression through the mammalian cell cycle requires the sequential activation of a series of cyclin dependent kinases. The activity of these kinases is regulated at several levels and the current challenge is to determine how the various signal transduction pathways are linked to the cell cycle machinery. An obvious focus is the so-called restriction point in late G1, and current evidence suggests that this is in part determined by the phosphorylation of the retinoblastoma protein (Rb) by the cyclin D dependent kinases, CDK4 and CDK6. Downstream targets of Rb, such as the E2F1 transcription factor, can promote cell cycle progression, whereas inhibitors of CDK4 and CDK6, such as p16CDKN2a, can block G1 progression. Many human tumours have been shown to have chromosomal abnormalities that directly affect components of this pathway, resulting in either the functional inactivation of p16 or Rb or the excessive activity of cyclin D1 or CDK4. Each of these lesions is likely to lead to unrestrained proliferation, and as they form part of a common pathway, they are generally mutually exclusive. Inhibitors of this pathway therefore have considerable promise as therapeutic agents.