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and PKC
in Mediating Calcineurin-Induced Transactivation1
Laboratory of Molecular Cell Biology, Science Applications International Corporation-Frederick, Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, MD 21702
T lymphocyte activation signals regulate the expression and
transactivation function of retinoid X receptor (RXR) 
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 RNA and
protein in T lymphocyte leukemia Jurkat cells and prevented
activation-induced RXR 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 expression and even augmented activation-induced RXR
expression. Expression of a dominant-active (DA) mutant of CN together
with a DA mutant of protein kinase C (PKC)
, a novel PKC isoform,
significantly increased RXRE-dependent transcription. Expression of
catalytically inactive PKC or a dominant-negative mutant of
PKC failed to synergize with CN and did not increase RXRE-dependent
transcription. Expression of a DA mutant of PKC or treatment with
PMA was found to attenuate PKC and CN synergism. We conclude that
PP1, PP2A, and CN regulate levels and transcriptional activation
function of RXR in T cells. In addition, CN synergizes
with PKC to induce RXRE-dependent activation, a cooperative function
that is antagonized by the activation of the conventional
PKC isoform. Thus, PKC and PKC may function as positive and
negative modulators, respectively, of CN-regulated RXRE-dependent
transcription during T cell activation.
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