The promoter of the rat 3-hydroxy-3-methylglutaryl coenzyme A reductase gene contains a tissue-specific estrogen-responsive region

The isoprenoid metabolic pathway is mainly regulated at the level of conver sion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to mevalonate, cata lyzed by HMG CoA reductase. As estrogens are known to influence cholesterol metabolism, we have explored the potential regulation of the HMG CoA reduc tase gene promoter by estrogens. The promoter contains an estrogen-responsi ve element-like sequence at position -93 (termed Red-ERE), which differs fr om the ERE consensus by one mismatch in each half of the palindrome. A Red- ERE oligonucleotide specifically bound estrogen receptor in vitro and confe rred receptor-dependent estrogen responsiveness to a heterologous promoter in all cell lines tested. However, expression of a reporter driven by the r at HMG CoA reductase promoter was induced by estrogen treatment after trans ient transfection into the breast cancer cell line MCF-7 cells but not in h epatic cell lines expressing estrogen receptor. Estrogen induction in MCF-7 cells was dependent on the Red-ERE and was strongly inhibited by the antie strogen ICI 164,384. A functional cAMP-responsive element is located immedi ately upstream of the Red-ERE, but cAMP and estrogens inhibit each other in terms of transactivation of the promoter. Similarly, induction by estrogen s was inhibited by micromolar concentrations of cholesterol, likely acting via changes in occupancy of the sterol-responsive element located 70 bp ups tream of the Red-ERE. Thus, within its natural context, Red-ERE is able to mediate hormonal regulation of the HMG CoA reductase gene in tissues that r espond to estrogens with enhanced cell proliferation, while it is not opera tive in liver cells. Mle postulate that this tissue-specific regulation of HMG CoA reductase by estrogens could partially explain the protective effec t of estrogens against heart disease.