title: Regulation of retinoid X receptor responsive element-dependent transcription in T lymphocytes by Ser/Thr phosphatases: functional divergence of protein kinase C (PKC)theta; and PKC alpha in mediating calcineurin-induced transactivation.
abstract: T lymphocyte activation signals regulate the expression and transactivation function of retinoid X receptor (RXR) alpha through an interplay of complex signaling cascades that are not yet fully understood. We show that cellular Ser/Thr protein phosphatases (PPs) play an important role in mediating these processes. Inhibitors specific for PP1 and PP2A decreased basal expression of RXR alpha RNA and protein in T lymphocyte leukemia Jurkat cells and prevented activation-induced RXR alpha accumulation in these cells. In addition, these inhibitors attenuated the RXR responsive element (RXRE)-dependent transcriptional activation in transient transfection assays. Inhibitors of calcineurin (CN), by contrast, did not have any effect on the basal RXR alpha expression and even augmented activation-induced RXR alpha expression. Expression of a dominant-active (DA) mutant of CN together with a DA mutant of protein kinase C (PKC)theta;, a novel PKC isoform, significantly increased RXRE-dependent transcription. Expression of catalytically inactive PKC theta; or a dominant-negative mutant of PKC theta; failed to synergize with CN and did not increase RXRE-dependent transcription. Expression of a DA mutant of PKC alpha or treatment with PMA was found to attenuate PKC theta; and CN synergism. We conclude that PP1, PP2A, and CN regulate levels and transcriptional activation function of RXR alpha in T cells. In addition, CN synergizes with PKC theta; to induce RXRE-dependent activation, a cooperative function that is antagonized by the activation of the conventional PKC alpha isoform. Thus, PKC theta; and PKC alpha may function as positive and negative modulators, respectively, of CN-regulated RXRE-dependent transcription during T cell activation.
authors.affiliation: Laboratory of Molecular Cell Biology, Science Applications International Corporation-Frederick, Frederick Cancer Research and Development Center, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. mishaq@nih.gov
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ishaq
authors.forename: Ming
authors.initials: M
authors.lastname: Fan
authors.forename: Kip
authors.initials: K
authors.lastname: Wigmore
authors.forename: Arunasri
authors.initials: A
authors.lastname: Gaddam
authors.forename: Ven
authors.initials: V
authors.lastname: Natarajan
mesh_terms: D019703:Calcineurin / Q000378:metabolism* / Q000502:physiology; D065095:Calcineurin Inhibitors; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D019169:Jurkat Cells; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051571:Protein Kinase C-alpha; D000074121:Protein Kinase C-theta; D054645:Protein Phosphatase 1; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000276:immunology*; D047488:Retinoid X Receptors; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology*
chemical_list: D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D019319:Okadaic Acid; C496628:PRKCA protein, human; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D000074121:Protein Kinase C-theta; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D013755:Tetradecanoylphorbol Acetate