Induction of hTERT expression and telomerase activity by estrogens in human ovary epithelium cells

In mammals, molecular mechanisms and factors involved in the tight regulati on of telomerase expression and activity are still largely undefined. In th is study, we provide evidence for a role of estrogens and their receptors i n the transcriptional regulation of hTERT, the catalytic subunit of human t elomerase and, consequently, in the activation of the enzyme. Through a com puter analysis of the hTERT 5'-flanking sequences, we identified a putative estrogen response element (ERE) which was capable of binding in vitro huma n estrogen receptor alpha (ER alpha). In vivo DNA footprinting revealed spe cific modifications of the ERE region in ER alpha-positive but not ER alpha -negative cells upon treatment with 17 beta-estradiol (E2), indicative of e strogen-dependent chromatin remodelling. In the presence of E2, transient e xpression of ER alpha but not ER beta remarkably increased hTERT promoter a ctivity, and mutation of the ERE significantly reduced this effect. No telo merase activity was detected in human ovary epithelial cells grown in the a bsence 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 para llel with enzymatic activity. This prompt estrogen modulation of telomerase activity substantiates estrogen-dependent transcriptional regulation of th e hTERT gene. The identification of hTERT as a target of estrogens represen ts a novel finding which advances the understanding of telomerase regulatio n in hormone-dependent cells and has implications for a potential role of h ormones in their senescence and malignant conversion.