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J. Biol. Chem., Vol. 276, Issue 34, 31978-31985, August 24, 2001
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From the Department of Physiology, McGill University,
Montréal, Québec H3G 1Y6, Canada
Activity-dependent changes in gene
expression involving the transcription factor cAMP-response
element-binding protein (CREB) occur in learning and memory, pain, and
drug addiction. This mechanism may also be important for
cytomegaloviral infections of the brain. The human cytomegalovirus
major immediate-early promoter/enhancer (hCMV promoter), rate-limiting
for productive cytomegalovirus infection, contains five cAMP-response
elements (CREs). Indirect evidence suggests that this promoter does not
function in unstimulated neurons. Here we test the hypothesis that
expression from the hCMV promoter in neurons is induced by membrane
depolarization. For these experiments, we infected cultured sympathetic
and hippocampal neurons with hCMV-green fluorescent protein (GFP)
promoter/reporter constructs using adenoviral gene transfer techniques
and measured transgene expression by quantifying GFP fluorescence and
GFP mRNA levels. We found that depolarization up-regulates promoter
activity by >90-fold. Moreover, our results from pharmacological
experiments suggest that this induction occurred through a
CREB-dependent pathway. Importantly, site-directed
mutagenesis of all five CREs in the promoter blocked this up-regulation
almost completely, whereas mutating four of them had no effect. We
conclude that the hCMV promoter acts as a molecular switch in neurons
and is strongly induced by membrane depolarization, neuronal activity, or other stimuli that activate CREB. These results may provide insight
into molecular mechanisms of cytomegalovirus-related diseases of the brain.
To whom correspondence should be addressed: Dept. of Physiology,
McGill University, McIntyre Medical Science Bldg., 3655 Promenade Sir
William Osler, Montréal, Québec H3G 1Y6, Canada. Tel.:
514-398-4334; Fax: 514-398-7452; E-mail: Ecooper@med.mcgill.ca.
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