Cell-cycle inhibitors: three families united by a common cause

In the cellular program leading to DNA synthesis, signals that drive cells into S-phase converge at the level of CDK activity. The products of at leas t three different gene families, Ink4, Cip/Kip and the pRb pocket-protein f amily, suppress S-phase entry. Ink4 proteins act by antagonizing the format ion and activation of cyclin D-CDK4 complexes, of which the ultimate downst ream target as related to S-phase entry appears to be pRb. Cip/Kip inhibito rs impinge upon that pathway by inhibiting CDK2 kinases that participate in the inactivation of pRb and, like cyclin E, may also have roles independen t of pRb. How the activities of these three classes of proteins are coordin ated remains obscure. In recent years, development of mouse models has acce lerated the elucidation of this complex network, showing roles that are som etimes cooperative and sometimes overlapping. We will discuss the interrela tionships between Cip/Kip inhibitors and the components of the pRb pathway, and how their activities ultimately regulate cell proliferation. (C) 2000 Published by Elsevier Science B.V. All rights reserved.