Induction of hTERT Expression and Telomerase Activity by Estrogens in Human Ovary Epithelium Cells

doi:10.1128/MCB.20.11.3764-3771.2000

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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 stilllargely undefined. In this study, we provide evidence for a roleof estrogens and their receptors in the transcriptional regulationof hTERT, the catalytic subunit of human telomerase and, consequently,in the activation of the enzyme. Through a computer analysis ofthe hTERT 5'-flanking sequences, we identified a putative estrogenresponse element (ERE) which was capable of binding in vitro humanestrogen receptor $alpha$ (ER $alpha$ ). In vivo DNA footprinting revealed specificmodifications of the ERE region in ER $alpha$ -positive but not ER $alpha$ -negativecells upon treatment with 17 $beta$ -estradiol (E2), indicative of estrogen-dependentchromatin remodelling. In the presence of E2, transient expressionof ER $alpha$ but not ER $beta$ remarkably increased hTERT promoter activity,and mutation of the ERE significantly reduced this effect. Notelomerase activity was detected in human ovary epithelial cellsgrown in the absence of E2, but the addition of the hormone inducedthe enzyme within 3 h of treatment. The expression of hTERT mRNAand protein was induced in parallel with enzymatic activity. Thisprompt estrogen modulation of telomerase activity substantiatesestrogen-dependent transcriptional regulation of the hTERT gene.The identification of hTERT as a target of estrogens representsa novel finding which advances the understanding of telomeraseregulation in hormone-dependent cells and has implications fora potential role of hormones in their senescence and malignantconversion.

^* 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 OncogenesisLaboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro156, 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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