Progression of normal cells from the quiescent state into the cell cycle requires passage through the so-called restriction point in the late G1-phase. Here, we summarize evidence suggesting that the regulatory cascade around the product of the retinoblastoma susceptibility gene (pRb) is the regulator of the restriction point. The autoregulatory feedback pathway involves pRb itself, cdk4/6, D-type cyclins and the cdk4/6-specific kinase inhibitors of the p16 family, with D-type cyclins meeting best the criteria for the restriction point regulator. Moreover, most recent data from tumor cell biology suggest that one of the members of this regulatory pathway has to become deregulated to allow for tumor growth. Thus, tumor development requires the loss of certain growth-regulating pathway(s) which is achieved by alternative loss of tumor suppressors (e.g. Rb or p16) or hyperactivity of proto-oncogenic counterparts (like cyclin D1 and cdk4). Deregulation of the Rb pathway probably occurs in every tumor either as an initiating or as a progression-promoting event.

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