INACTIVATION OF A CDK2 INHIBITOR DURING INTERLEUKIN 2-INDUCED PROLIFERATION OF HUMAN T-LYMPHOCYTES

Peripheral blood T lymphocytes require two sequential mitogenic signal s to reenter the cell cycle from their natural, quiescent state. One s ignal is provided by stimulation of the T-cell antigen receptor, and t his induces the synthesis of both cyclins and cyclin-dependent kinases (CDKs) that are necessary for progression through G(1). Antigen recep tor stimulation alone, however, is insufficient to promote activation of G(1) cyclin-Cdk2 complexes. This is because quiescent lymphocytes c ontain an inhibitor of Cdk2 that binds directly to this kinase and pre vents its activation by cyclins. The second mitogenic signal, which ca n be provided by the cytokine interleukin 2, leads to inactivation of this inhibitor, thereby allowing Cdk2 activation and progression into S phase. Enrichment of the Cdk2 inhibitor from G(1) lymphocytes by cyc lin-CDK affinity chromatography indicates that it may be p27(Kip1). Th ese observations show how sequentially acting mitogenic signals can co mbine to promote activation of cell cycle proteins and thereby cause c ell proliferation to start. CDK inhibitors have been shown previously to be induced by signals that negatively regulate cell proliferation. Our new observations show that similar proteins are down-regulated by positively acting signals, such as interleukin 2. This finding suggest s that both positive and negative growth signals converge on common ta rgets which are regulators of G(1) cyclin-CDK complexes. Inactivation of G, cyclin-CDK inhibitors by mitogenic growth factors may be one bio chemical pathway underlying cell cycle commitment at the restriction p oint in G(1).