Interdependence of cdk2 activation and interleukin-2Ralpha accumulation in T cells.
We have shown previously that serum promotes T cell proliferation by acting with T cell receptor (TCR) agonists to efficiently down-regulate p27(Kip1) and activate cdk2-containing complexes. In the studies described here, the effect of serum on the expression of the alpha subunit of the interleukin-2 receptor (IL-2Ralpha) was examined. We found that serum was required for maximal and sustained IL-2Ralpha protein expression and consequent IL-2 signaling in TCR-activated splenocytes. Serum had no effect on IL-2Ralpha mRNA levels and thus modulates IL-2Ralpha expression post-transcriptionally. Unlike wild-type splenocytes, splenocytes exhibiting serum-independent cdk2 activation due to loss of p27(Kip1) efficiently expressed IL-2Ralpha in serum-deficient medium. Conversely, serum did not promote IL-2Ralpha accumulation in conditions in which cdk2 activity was blocked. These findings demonstrate that cdk2 activation is necessary and sufficient for IL-2Ralpha accumulation in TCR-stimulated splenocytes. On the other hand, IL-2 signaling was required (at least in part) for cdk2 activation in these cells. Thus, cdk2 activation, IL-2Ralpha expression, and IL-2 signaling are interdependent events, and we suggest that this feed-forward regulatory loop plays a key role in T cell mitogenesis.
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Oncology, , University of South Florida College of Medicine, Tampa, Florida 33612, USA.
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Mohapatra
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Pledger
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000276:immunology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000235:genetics*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D014158:Transcription, Genetic; D015854:Up-Regulation
D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases