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

T lymphocyte activation signals regulate the expression and transactivation function of retinoid X receptor (RXR) a 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 RXRalpha RNA and protein in T lymphocyte leukemia Jurkat cells and prevented activation-induced RXRalpha 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 RXRalpha expression and even augmented activation-induced RXRalpha expression. Expression of a dominant-active (DA) mutant of CN together with a DA mutant of protein kinase C (PKQ)theta, a novel PKC isoform, significantly increased RXRE-dependent transcription. Expression of catalytically inactive PKCtheta or a dominant-negative mutant of PKCtheta failed to synergize with CN and did not increase RXRE-dependent transcription. Expression of a DA mutant of PKCalpha or treatment with PMA was found to attenuate PKCtheta and CN synergism. We conclude that PP1, MA, and CN regulate levels and transcriptional activation function of RXRa in T cells. In addition, CN synergizes with PKCtheta to induce RXRE- dependent activation, a cooperative function that is antagonized by the activation of the conventional PKCalpha isoform. Thus, PKCtheta and PKCalpha may function as positive and negative modulators, respectively, of CN-regulated RXRE- dependent transcription during T cell activation.

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