G1/S control and its deregulation in cancer

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Cancer is increasingly viewed as a cell-cycle disease, a notion supported by recent accumulation of data on the molecular basis of the cell-cycle machinery and its defects commonly found in human tumours including breast carcinomas. Strikingly, the cell-cycle phase targeted most frequently in multistep oncogenesis is the control of G1/S transition. This period includes the late-G1 commitment to replicate the genome and complete the cycle (the restriction point control), and the initiation of DNA replication, events regulated by the so-called `RB pathway'. While the key components of the RB pathway qualify as proto-oncogenes or tumour suppressors, and their aberrations may provide direct proliferative advantage to cancer cells, defects in the so-called checkpoint mechanisms that monitor and help ensure the error-free execution of the cell-cycle transitions act more indirectly, yet affect both tumour progression and response to anti-cancer therapy.

Examples of both the oncogenic defects in the G1/S-controlling machinery, and the ways proto-oncogenic events may activate checkpoint responses, will be presented. In addition, evidence in favour of the existence of a parallel pathway, independent of and cooperating with the classical p16-cyclin D/CDK-pRB-E2F axis (the RB pathway) to govern timely S-phase entry, will be reported. Finally, the proposed candidacy of the RB pathway for the molecular mechanism underlying the late-G1 restriction point switch will be critically considered, and emerging data on novel functions of the RB pathway in coordination of the cell cycle events from late G1 until mitosis will be summarized. These new discoveries have significant implications for our understanding of the mammalian cell-cycle control and its subversion in tumour cells, with emerging applications in tumour diagnosis, prognosis, and attempts to device new strategies to treat cancer.