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Molecular and Cellular Biology, June 2000, p. 3764-3771, Vol. 20, No. 11
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

Silvia Misiti,1 Simona Nanni,1 Giulia Fontemaggi,1 Yu-Sheng Cong,2 Jianping Wen,2 Hal W. Hirte,3 Giulia Piaggio,1 Ada Sacchi,1 Alfredo Pontecorvi,1,4 Silvia Bacchetti,2,* and Antonella Farsetti1,5,*

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 alpha  (ERalpha ). In vivo DNA footprinting revealed specific modifications of the ERE region in ERalpha -positive but not ERalpha -negative cells upon treatment with 17beta -estradiol (E2), indicative of estrogen-dependent chromatin remodelling. In the presence of E2, transient expression of ERalpha but not ERbeta 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.

Molecular and Cellular Biology, June 2000, p. 3764-3771, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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