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

• Published in: The Journal of immunology (1950) 2002-07, Vol.169 (2), p.732-738
• Main Authors: Ishaq, M, Fan, M, Wigmore, K, Gaddam, A, Natarajan, V
• Format: Article
• Language: English
• ISSN: 0022-1767

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.