Estrogen Stimulates Estrogen-Related Receptor α Gene Expression through Conserved Hormone Response Elements

Abstract

The estrogen-related receptor alpha gene encodes a nuclear receptor protein, ERR alpha, whose structure is closely related to the estrogen receptors. ERR alpha modulates estrogen receptor (ER)-mediated signaling pathways both positively and negatively. It is selectively expressed in a variety of cell types during development and in adult tissues. We have previously shown that estrogen stimulates the expression of the ERR alpha gene in mouse uterus. In this study, we found that the ERR alpha gene is stimulated by estrogen in mouse uterus and heart but not in liver. Estrogen also stimulates the expression of ERR alpha in the human breast and endometrial cell lines. The human ERR alpha gene promoter contains multiple Sp1 binding sites, and the Sp1 protein is required for the promoter activity. The major estrogen response is mediated by a 34-bp DNA element that contains multiple steroid hormone response element half-sites (MHREs) that are conserved between the human and mouse ERR alpha gene promoters. Mutations made at a single or multiple sites of the MHREs abolished the ER-mediated transcription of the element in transient transfection experiments. By chromatin immunoprecipitation assay, we demonstrated the interaction between ER alpha and MHREs of the endogenous ERR alpha gene promoter in MCF-7 cells. Estrogen treatment further enhanced the association of ER alpha and MHREs in vivo. The present study demonstrated that the ERR alpha gene is a downstream target of ER alpha.

Estrogen Induces Estrogen-related Receptor α Gene Expression and Chromatin Structural Changes in Estrogen Receptor (ER)-positive and ER-negative Breast Cancer Cells

“…The ERR␣ Gene MHRE Is Assembled Over a Single Nucleosome-We demonstrated previously that estrogen stimulation of the ERR␣ expression is mediated through the MHRE located between bp Ϫ709 to Ϫ649 of the ERR␣ promoter (51,63). To study the influence of estrogen on the chromatin dynamics in this portion of the ERR␣ promoter, we had to first determine the nucleosome positions around the MHRE region.…”

“…Restriction enzymes were purchased from New England Biolabs (Beverly, MA) and micrococcal nuclease (MNase) from Worthington. The plasmid 0.8-CAT that contains 0.8-kb of the ERR␣ promoter (51), the plasmid h55 that contains the entire ERR␣ promoter sequence, 3 and AAB-CAT reporter plasmid were all constructed in our laboratory (51,56). Antibodies for antiacetylhistone H3 (K9 and K14), anti-acetylhistone H4 (K5, K8, K12, and K16), anti-ER␣ (HC-20), anti-c-Jun (sc-45x), anti-RNA polymerase II (N-20), anti-P300 (C-20), anti-CBP (A-22), and anti-RIP140 (H-300) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA).…”

“…1), and probe B was radiolabeled by random priming (Ready-to-Go beads; GE Healthcare) of the PstI/SphI genomic fragment ( Fig. 1) (51,56). Hybridization was carried out overnight at 65°C, and the blots washed and then exposed to x-ray film at Ϫ70°C.…”

“…ERR␣ may promote the growth of breast cancers by increasing local estrogen synthesis as it is reported to stimulate the expression of CYP19A1 (P450 aromatase) (48,49) and SULT2A1 (50), enzymes that contribute to estrogen biosynthesis. Furthermore, we have previously demonstrated that the ERR␣ gene, ESRRA, is an ER-dependent estrogen target in certain estrogen-responsive tissues and cell lines (21,51). At this time, however, the contribution of ERR␣ to hormone resistance and tumor progression in breast cancers remains unknown but may have vital clinical implications.…”

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E2– and cAMP‐dependent pathways in osteoarthritic chondrocytes

“…ERR␣ is regulated by estrogen in many tissues, including bone, and ER␣ binds the ERR␣ promoter and activates its expression (44,45). Accumulating evidence supports a role of estrogen in adult joint tissues but, similar to ERR␣, estrogen may have dual effects (46,47).…”