NEW CELL-CYCLE REGULATORS - THE CDK-CYCLI NS MODULATORY PROTEINS

A few years after identification of the universal factor that controls onset of mitosis in all eukaryotic cells, MPF (M-phase promoting fact or), as the cyclin B-cdc2 kinase, it has become apparent that all tran sitions of the cell cycle are controlled by a series of kinase complex es between cdc2-related cyclin-dependent kinases (cdk) and their respe ctive regulatory cyclin subunits. While the phosphorylation of Thr161 in cdc2 (or its homologue in the other cdks) appears as a prerequisite for maximal activity of the cyclin-kinases, phosphorylation on Thr14 and Tyr15 exerts an inhibitory action on cyclin B-cdc2 but likely not on the other complexes in vivo. A recent flurry of reports reveals the existence of a variety of small proteins which bind to and modulate G 1/S cdk-cyclin complexes. In mammalian cells, 5 different regulators, p15, p16, p21, p24 and p27, have been identified so far, being mainly inhibitors. They are believed to delay activation of cdk-cyclins to ma intain a temporal order of cdk activation during progression of G1. So me of these inhibitors have been shown to be particularly involved in certain circumstances : p21, whose synthesis is induced by p53, causes G1 cell-cycle arrest following DNA damage or in senescent or quiescen t cells. These effects seem essentially the consequence of the inhibit ory action of p21 on cdk2-cyclin E complexes but p21 is possibly a uni versal cdk-cylin regulator. p27 induces G1 arrest in contact-inhibited and in TGF beta- or cyclic AMP-treated cells by inhibiting particular ly cdk2-cyclin E and/or cdk4-cyclin D. p15, whose synthesis is induced by TGF beta, and p16 bind cdk4 as well as cdk6 and appear as new pote ntial tumor suppressors. p24 has homology to dual protein phosphatases and associates to cdc2, cdk2 and cdk3.