IL-2-dependent induction of G1 cyclins in primary T cells is not blocked by rapamycin or cyclosporin A.
Autocrine stimulation of the IL-2 receptor (IL-2R) is required for commitment of a T cell to enter the cell cycle and may involve transmission of the IL-2R signal to cell cycle control proteins. Candidates for such proteins are the D-type cyclins which are expressed in G1. Short-term cultures of primary human T cells were used to show that expression of cyclins D2 and D3 is regulated by IL-2 in a concentration- and time-dependent manner. Cyclin D2 RNA was induced rapidly to peak levels well before initiation of DNA synthesis and gradually declined during the remainder of G1. Cyclin D3 RNA and protein showed a slower induction during G1 to maximal levels as cells initiated DNA synthesis that remained high throughout S phase. Induction of cyclins D2 and D3 was independent of the cyclosporin A-sensitive calcineurin pathway and of rapamycin-sensitive pathways, despite the ability of rapamycin to severely inhibit entry into S phase. These observations suggest that cyclins D2 and D3 may monitor the IL-2R signal but that their induction does not guarantee entry into S phase. Rapamycin was found to target a pathway late in G1 that is distal to induction of D-type cyclin gene expression but proximal to DNA replication, perhaps involving the function of the D-type cyclin proteins or their associated kinases.
Turner
J M
JM
Department of Pathology, University of Cambridge, UK.
D002478:Cells, Cultured; D016213:Cyclins / Q000235:genetics*; D016572:Cyclosporine / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D005434:Flow Cytometry; D016193:G1 Phase; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D011090:Polyenes / Q000494:pharmacology*; D015375:Receptors, Interleukin-2 / Q000032:analysis; D020123:Sirolimus; D013601:T-Lymphocytes / Q000187:drug effects
D016213:Cyclins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011090:Polyenes; D015375:Receptors, Interleukin-2; D016572:Cyclosporine; D004247:DNA; D020123:Sirolimus