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and Cyclic Adenosine 5'-Monophosphate Response Element Binding Protein1
Centre de Recherche en Infectiologie, Hôpital CHUL, Centre Hospitalier Universitaire de Québec, and Département de Biologie Médicale, Faculté de Médecine, Université Laval, Ste-Foy, Québec, Canada
Previous work indicates that treatment of human T cells with
PGE2 results in an increase of HIV-1 long terminal repeat
(LTR) transcriptional activity. The noticed PGE2-mediated
activation of virus gene activity required the participation of
specific intracellular second messengers such as calcium and two
transcription factors, i.e., NF-
B and CREB. We report in this work
that the nuclear transcription factor CCAAT/enhancer binding protein
(C/EBP) is also important for PGE2-dependent up-regulation
of HIV-1 LTR-driven gene activity. The implication of C/EBP was shown
by using a trans-dominant negative inhibitor of C/EBP
(i.e., liver-enriched transcriptional inhibitory protein) and
several molecular constructs carrying site-directed mutations in the
C/EBP binding sites located within the HIV-1 LTR. Mutated HIV-1 LTR
constructs also revealed the involvement of the two most proximal C/EBP
binding sites. Data from cotransfection experiments with vectors coding
for dominant negative mutants and gel mobility shift assays indicated
that PGE2-mediated induction of HIV-1 LTR activity results
from a cooperative interaction between C/EBP
and CREB, two members
of the basic leucine zipper family of transcription factors. Altogether
these findings indicate that treatment of human T cells with
PGE2 induces HIV-1 LTR activity through a complex interplay
between C/EBP
and CREB. Such a combinatorial regulation may
represent a mechanism that permits a fine regulation of HIV-1
expression by PGE2 in human T cells.
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