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Vol. 11, Issue 12, 4381-4391, December 2000
and
*Laboratory of Molecular Medicine, Department of Nephrology, Rambam
Medical Center, Haifa 31096, Israel; and Three different cell differentiation experimental model systems
(human embryonic stem cells, mouse F9 cells, and human HL-60 promyelocytic cells) were used to determine the relationship between the reduction in telomerase activity after differentiation and the
regulation of the promoter for the hTERT gene. Promoter constructs of
three different lengths were subcloned into the PGL3-basic luciferase
reporter vector. In all three experimental systems, all three promoter
constructs drove high levels of reporter activity in the
nondifferentiated state, with a marked and time-dependent reduction
after the induction of differentiation. In all cases, the smallest core
promoter construct (283 nt upstream of the ATG) gave the highest
activity. Electrophoretic mobility shift assays revealed transcription
factor binding to two E-box domains within the core promoter. There was
also a marked time-dependent reduction in this binding with
differentiation. In addition, a distinct and novel element was
identified within the core promoter, which also underwent
time-dependent reduction in transcription factor binding with
differentiation. Site-directed mutagenesis of this novel element
revealed a correlation between transcription factor binding and
promoter activity. Taken together, the results indicate that regulation
of overall telomerase activity with differentiation is mediated at
least in part at the level of the TERT promoter and provides new
information regarding details of the regulatory interactions that are
involved in this process.
Bruce
Rappaport Faculty of Medicine and Research Institute, Technion, Israel
Institute of Technology, Haifa 31096, Israel
Corresponding author. E-mail address:
bimaty{at}tx.technion.ac.il.
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