Differential requirements for interleukin-2 distinguish the expression and activity of the cyclin-dependent kinases Cdk4 and Cdk2 in human T cells.
We examined the expression and activity of Cdk4 and Cdk2 in resting, competent, and proliferating normal human T cells. Expression of Cdk4 but not of Cdk2 was induced in competent T cells independent of an IL-2 signal. This up-regulation of Cdk4 mRNA and protein was resistant to the immunosuppressant drugs cyclosporin A (CsA) and FK506. A further increase in Cdk4 expression was seen upon stimulation of competent T cells by IL-2, as was de novo expression of Cdk2. Cyclin D2, a Cdk4 partner, showed similar patterns of regulation as Cdk4. The increases in Cdk4 and cyclin D2 expression seen in competent T cells were functionally significant since Cdk4 immunoprecipitates from these cells phosphorylated recombinant RB protein in vitro. Despite the lack of an increase in the expression of Cdk2, a small pool of pre-existing Cdk2 protein detected in resting T cells could be activated upon induction of competence. These data demonstrate that 1) the signals that lead to induction of competence in T cells stimulate an IL-2-independent and CsA-resistant phase of Cdk4 and cyclin D2 expression, Cdk4 kinase activity, and Cdk2 kinase activity, and 2) IL-2 stimulates a second phase of Cdk4 and cyclin D2 expression and de novo expression of Cdk2 in these cells. The data show that the expression and activity of these major cell cycle regulatory proteins are controlled differentially by growth factors and indicate a role for Cdk4 and cyclin D2 in T-cell cycle entry and/or early G1 progression and for Cdk2 in later G1 progression and G1/S transition.
Modiano
J F
JF
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206.
Domenico
J
J
Szepesi
A
A
Lucas
J J
JJ
Gelfand
E W
EW
D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D056742:Cyclin D2; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology*
C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases