Progesterone regulates human telomerase reverse transcriptase gene expression via activation of mitogen-activated protein kinase signaling pathway

Emerging evidence indicates that sex steroid hormones regulate telomerase i n target tissues. We have reported that estrogen activates telomerase throu gh transactivation of the telomerase catalytic subunit, human telomerase re verse transcriptase (hTERT), Progesterone usually antagonizes estrogen acti on in reproductive organs, but the effect on telomerase remains unclear. In this study, we examine the effects of progesterone on the gene expression of hTERT in breast and endometrial cancer cell lines expressing progesteron e receptor. Progesterone significantly induced hTERT mRNA expression within 3 h after exposure. This transient effect peaked at 12 h and then decrease d. In contrast, exposure to progesterone for >48 h antagonized estrogen eff ects and inhibited the estrogen-induced activation of hTERT expression; the cyclin-dependent kinase inhibitor p21/Waf1/Cip1 plays an integral role in this inhibition. Thus, progesterone exerts diverse effects on hTERT mRNA ex pression in a time-dependent manner. We also found that the mitogen-activat ed protein kinase signaling pathway mediates both the short-term and long-t erm effects of progesterone on hTERT gene expression, These findings suppor t the notion that hTERT gene is a target of both estrogen and progesterone,