Coactivation of Estrogen Receptor β by Gonadotropin-Induced Cofactor GIOT-4

Abstract

Estrogen exerts its diverse effects through two subtypes of estrogen receptors (ER), ER␣ and ER␤. Each subtype has its own distinct function and expression pattern in its target tissues. Little, however, is known about the transcriptional regulatory mechanism of ER␤ in the major ER␤-expressing tissues. Using biochemical methods, we identified and described a novel ER␤ coactivator. This protein, designated GIOT-4, was biochemically purified from 293F cells. It coactivated ER␤ in ovarian granulosa cells. GIOT-4 expression was induced by stimulation with follicle-stimulating hormone (FSH). GIOT-4 recruited an SWI/SNF-type complex in a ligand-independent manner to ER␤ as an ER subtype-specific physical bridging factor and induced subsequent histone modifications in the ER␤ target gene promoters in a human ovarian granulosa cell line (KGN). Indeed, two ER␤-specific target genes were upregulated by FSH at a specific stage of a normal ovulatory cycle in intact mice. These findings imply the presence of a novel regulatory convergence between the gonadotropin signaling cascade and ER␤-mediated transcription in the ovary.Estrogen plays important roles in many target organs, including the female reproductive organs, the central nervous system, and bone. Estrogen exerts its diverse biological actions through binding to and activating one of two nuclear estrogen receptor (ER) subtypes (ER␣ or ER␤) (12,22,35,40). ERs are members of the nuclear receptor (NR) gene superfamily. ERs, bound to and activated by estrogen, bind to specific DNA sequences called estrogen-responsive elements (ERE) to induce target genes (14,21).Like the other NR members, the ER requires the cooperation of distinct classes of coregulators and multiprotein coregulator complexes in order to initiate estrogen-mediated chromatin reorganization (16,46). These complexes appear to modify the chromatin configuration in a highly regulated manner by controlling nucleosomal rearrangement and enzymecatalyzed modifications of histone tails. By altering chromatin structure, the coregulator complexes facilitate bridging between NRs and basal transcription factors, along with RNA polymerase II, thereby controlling transcription. As for the nucleosomal rearrangement, two major classes of chromatinmodifying complexes that coregulate NRs have been well-characterized. One class is the histone-modifying complexes, including discrete subfamilies of transcription coregulatory complexes (2,29,36). The best-characterized NR coregulator complexes possess either histone acetylase or histone deacetylase activities. Recently, histone methylases/demethylases have also been shown to be significant NR coregulators. The other class of coregulator complexes is ATP-dependent chromatinremodeling complexes. These complexes use ATP hydrolysis to rearrange nucleosomal arrays in a noncovalent manner to facilitate or prevent the access of NRs to nucleosomal DNA (5,17,33). These ATP-dependent chromatin-remodeling complexes have been classified into three subfamilies based on the major catalytic ...

Negative Regulation of Estrogen Signaling by ERβ and RIP140 in Ovarian Cancer Cells

“…Other coregulatory proteins have been shown to interact specifically with one receptor or the other. For instance, GIOT-4 and thyroid hormone receptor-associated protein 220 have been identified as ER␤-specific coactivators (48,49), whereas BRG1-and hBRM-Associated Factor 57 or calmodulin selectively regulates ER␣-mediated transcription (50,51). More recently, a comparative computational analysis of the nuclear interactomes of the 2 ER subtypes revealed only 70 common proteins (on a total of 498 partners), thus likely explaining the distinct biological roles of the 2 ERs (52).…”

Steroid Receptors in the Uterus and Ovary

“…127,373 Recent work in KGN cells suggest that GIOT-4, a cofactor regulated by FSH, may act to increase ERβ expression as well as work in combination with ERβ to regulate target genes in follicles. 423 Although this work was done primarily in KGN ovarian cells, it was also reported that GIOT-4 and ERβ are co-localized in growing follicles providing support for the co-regulation. The expression of GIOT-4 has not been examined in in vitro-cultured granulosa cells.…”

Dialogue between estrogen receptor and E2F signaling pathways: The transcriptional coregulator RIP140 at the crossroads

“…One of the hypotheses to explain the inhibitory effect of ERβ on E2 regulation of gene expression and cell proliferation implies a differential recruitment of transcriptional coregulators by the two ER subtypes. Previous studies have reported ERβ [54,55] or ERα [56,57]…”