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Protein Kinase A Regulatory Subunit Type II Directly Interacts with and Suppresses CREB Transcriptional Activity in Activated T Cells¹

Michael R. Elliott^*, Mate Tolnay, George C. Tsokos and Gary M. Kammer^2,*,

^* Department of Microbiology and Immunology and Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157; and Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910

Levels of the type II regulatory subunit (RII) of protein kinase A are abnormally high in the nuclei of T cells of some subjects with the autoimmune disorder systemic lupus erythematosus (SLE). However, the role of nuclear RII in the regulation of T cell function is unknown. Based on previous studies demonstrating that nuclear protein kinase A-RII subunits can modify cAMP response element (CRE)-dependent transcription, we tested the hypothesis that nuclear RII can alter CRE-directed gene expression in T cells through interaction with the nuclear transcription factor CRE-binding protein CREB. To test this hypothesis, we used the RII-deficient S49 and the Jurkat T cell lines. In both cell lines, transient transfection of RII resulted in nuclear localization of a portion of the ectopically expressed RII. In vitro and in vivo analyses revealed a novel, specific interaction between RII and CREB that mapped to the N-terminal 135 aa of RII. In functional studies, RII inhibited the transcriptional activity of a GAL4-CREB fusion protein by 67% in Jurkat T cells following activation with anti-CD3 and anti-CD28 mAbs. Importantly, deletion of the CREB-binding region of RII completely abrogated inhibition. Additionally, RII suppressed CRE-directed reporter gene expression and substantially reduced induction of promoter activity and endogenous protein levels of the CREB-dependent gene, c-fos, in activated T cells. We conclude that nuclear RII can act as a repressor of CREB transcriptional activity in T cells, providing a potential functional significance for aberrant levels of nuclear RII in systemic lupus erythematosus T cells.

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The JI 2003 171: 3317-3318. [Full Text]  

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