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Centre de Recherche en Infectiologie, Hôpital Centre Hospitalier de l’Université Laval, Centre Hospitalier Universitaire de Québec, and Département de Biologie Médicale, Faculté de Médecine, Université Laval, Ste-Foy, Quebec, Canada
HIV-1 gene regulation is greatly dependent on the presence
of the -104/-81 enhancer region which is regulated by both NF-
B
and NFAT transcription factors. We have found that a greater induction
in HIV-1 long terminal repeat-driven gene expression was observed upon
PMA/ionomycin (Iono) stimulation of a CD45-deficient cell line (J45.01)
in comparison to the parental Jurkat cells. Unlike NF-B which was
not affected by the absence of CD45, NFAT showed a much greater
augmentation in nuclear translocation and transcriptional activity in
J45.01 cells upon PMA/Iono stimulation. PMA/Iono-induced NFAT
activation, NFAT translocation and calcium influx peaked at similar
time points for both Jurkat and J45.01 cell lines. The NFAT-dependent
promoters from the IL-2 and TNF-
genes were
also more potently activated by PMA/Iono in J45.01 cells.
Interestingly, higher levels of intracellular calcium were consistently
demonstrated in PMA/Iono-induced CD45-deficient cell lines (J45.01 and
HPB45.0). Furthermore, PMA/Iono induction of calcium mobilization in
both Jurkat and J45.01 cell lines was observed to be EGTA-sensitive.
Mechanistic studies revealed that CD3
and ZAP-70 were more heavily
tyrosine phosphorylated in J45.01 cells than Jurkat cells. Analysis of
the HIV-1 enhancer by EMSAs demonstrated that the bound NFAT complex
was present at higher levels in J45.01 nuclear extracts and that the
NFAT1 member was predominant. In conclusion, our results indicate that
NFAT activation by stimuli acting in a more distal fashion from the
TCR-mediated signaling pathway can be down-regulated by CD45 and that
this CD45-dependent regulation in turn affects HIV-1 long terminal
repeat activation.
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