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Papers In Press, published online ahead of print June 7, 2001
Department of Physiology, McGill University, Montreal, PQ H3G 1Y6
Corresponding Author: ecooper{at}med.mcgill.ca
Activity-dependent changes in gene expression involving the transcription factor 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 cyclic AMP 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-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.
J. Biol. Chem, 10.1074/jbc.M103667200
Submitted on April 24, 2001
Revised on June 4, 2001
Accepted on June 7, 2001
Depolarization strongly induces human CMV major immediate-early promoter/enhancer activity in neurons
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