Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes.
Lymphocyte proliferation is key to the regulation of the immune system. Cyclin D2 is the first cell cycle protein induced following stimulation through the T-cell receptor, the B-cell receptor or cytokines. The promoter of this cyclin integrates a diverse range of signals. Through investigating the regulation of this promoter by interleukin-2 and phosphatidylinositol 3-kinase, we have identified a role for the transcription factor CREB, cAMP response element-binding protein. Mutation of the CREB-binding site reduced cyclin D2 promoter activity 5-10-fold. CREB-1 is phosphorylated at serine 133, a critical site for activity, in both T cells and Epstein-Barr virus immortalized B cells. The introduction of an S133A mutant of CREB-1 reduces IL-2 induction of cyclin D2 promoter activity, demonstrating a role for this phosphorylation site in promoter activity. Two inhibitors of protein kinase A reduce lymphocyte proliferation and CREB-1 phosphorylation. This study demonstrates that the cyclin D2 promoter is capable of being regulated by PI3K and CREB and identifies CREB-1 and protein kinase A as potential targets for altering lymphocyte proliferation.
White
P C
PC
Medical Biochemistry and Immunology, Henry Wellcome Building, Cardiff University, Heath Park, Cardiff, UK.
Shore
A M
AM
Clement
M
M
McLaren
J
J
Soeiro
I
I
Lam
E W-F
EW
Brennan
P
P
D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology*; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic
C080336:CCND2 protein, human; D002227:Carbazoles; D017362:Cyclic AMP Response Element-Binding Protein; D056742:Cyclin D2; D016213:Cyclins; D004791:Enzyme Inhibitors; D007211:Indoles; D007376:Interleukin-2; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; C057416:KT 5720; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide