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During Activation of Cycling Human T Lymphocytes: Modulation of RXRE Transactivation Function by Mitogen-Activated Protein Kinase Pathways1
Laboratory of Molecular Cell Biology, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702
We have previously reported that the activation of resting human
immature peripheral blood T (PBT) lymphocytes is associated with the
loss of retinoid X receptor 
(RXR) expression. In the present
study, we have demonstrated that, unlike resting cells, activation of
cycling human mature PBT lymphocytes, and T lymphocyte leukemia cell
lines is accompanied by the accumulation of RXR mRNA and protein.
Interestingly, cyclosporin A further augmented RXR expression,
indicating the involvement of calcineurin pathways in the process.
9-cis retinoic acid inhibited the accumulation,
suggesting that retinoids can regulate the synthesis of their own
receptors during T cell activation. Transfection analysis in Jurkat
cells, using RXRE-dependent reporter assays, showed that RXR
accumulated during T cell activation was transcriptionally inactive. To
investigate the mechanism of such inhibition, the role of two
mitogen-activated protein kinase pathways, c-Jun N-terminal kinase
(JNK) and extracellular signal-regulated kinase (ERK), in modulating
RXRE-dependent transcription, was explored. The expression of
constitutively active MAP/ERK kinase kinase 1 (MEKK1) inhibited
RXRE-dependent transcription, whereas dominant negative MEKK1 increased
the transcription, indicating the involvement of JNK signaling pathways
in the process. In contrast, expression of constitutively active
MEK1, which activates ERK pathway, enhanced RXRE-dependent activation.
When both were activated simultaneously, JNK pathway was dominant over
ERK pathway and resulted in inhibition of RXRE-mediated transcription.
These data demonstrate a dual regulatory control of RXR expression
during the activation of resting and cycling T lymphocytes and indicate
a dynamic balance between JNK and ERK pathways in modulating
RXRE-mediated transactivation.
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