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Molecular and Cellular Biology, June 2000, p. 3764-3771, Vol. 20, No. 11
Molecular Oncogenesis Laboratory, Regina
Elena Cancer Institute,1 and Institute
of Experimental Medicine, National Research
Council,5 Rome, and Institute of Medical
Pathology, Catholic University, Milan,4 Italy,
and Department of Pathology and Molecular
Medicine2 and Department of
Medicine,3 McMaster University, Hamilton,
Ontario, Canada
Received 10 November 1999/Returned for modification 21 December
1999/Accepted 2 March 2000
In mammals, molecular mechanisms and factors involved in the tight
regulation of telomerase expression and activity are still largely
undefined. In this study, we provide evidence for a role of estrogens
and their receptors in the transcriptional regulation of hTERT, the
catalytic subunit of human telomerase and, consequently, in the
activation of the enzyme. Through a computer analysis of the hTERT
5'-flanking sequences, we identified a putative estrogen response
element (ERE) which was capable of binding in vitro human estrogen
receptor
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Induction of hTERT Expression and Telomerase
Activity by Estrogens in Human Ovary Epithelium Cells
(ER
). In vivo DNA footprinting revealed specific modifications of the ERE region in ER
-positive but not
ER
-negative cells upon treatment with 17
-estradiol (E2),
indicative of estrogen-dependent chromatin remodelling. In the presence
of E2, transient expression of ER
but not ER
remarkably increased
hTERT promoter activity, and mutation of the ERE significantly reduced
this effect. No telomerase activity was detected in human ovary
epithelial cells grown in the absence of E2, but the addition of the
hormone induced the enzyme within 3 h of treatment. The expression
of hTERT mRNA and protein was induced in parallel with enzymatic
activity. This prompt estrogen modulation of telomerase activity
substantiates estrogen-dependent transcriptional regulation of the
hTERT gene. The identification of hTERT as a target of estrogens
represents a novel finding which advances the understanding of
telomerase regulation in hormone-dependent cells and has implications
for a potential role of hormones in their senescence and malignant conversion.
*
Corresponding author. Mailing address for Silvia
Bacchetti: Department of Pathology and Molecular Medicine, McMaster
University, Hamilton, Ontario L8N 3Z5, Canada. Phone: (905) 525-9140, ext. 22296. Fax: (905) 546-9940. E-mail:
bacchett{at}fhs.mcmaster.ca. Mailing address for Antonella
Farsetti: Molecular Oncogenesis Laboratory, Regina Elena Cancer
Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. Phone:
(39-06) 4985-2531. Fax: (39-06) 4180-526. E-mail:
farsetti{at}crs.ifo.it.
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