title: Estrogen-related Receptor β Reduces the Subnuclear Mobility of Estrogen Receptor α and Suppresses Estrogen-dependent Cellular Function.
abstract: Estrogen-related receptor (ERR) is a member of the nuclear receptor superfamily that has strong homology with estrogen receptor (ER) α. ERR has three subtypes (α, β, and γ) expressed in estrogen-sensitive organs, including ovary, breast, and brain. No endogenous ligands of ERRs have been identified, but these receptors share a common DNA element with ERα and control estrogen-mediated gene transcription. Recent evidence suggests a role of ERRs in estrogen-related pathophysiology, but the detailed mechanisms of ERR functions in estrogen-related tissues are unclear. Using live-cell imaging with fluorescent protein labeling, we found that only ERRβ among the ERRs exhibits a punctate intranuclear pattern overlapping with ERα following 17β-estradiol (E2)-stimulation. Fluorescence recovery after photobleaching showed significant reduction of the mobility of ligand-activated ERα with co-expression of ERRβ. Fluorescence resonance energy transfer revealed that ERRβ directly interacts with ERα. The N-terminal domain of ERRβ was identified as the region that interacts with ERα. We also found a correlation between punctate cluster formation of ERα and interaction between the receptors. Expression of ERRβ significantly repressed ERα-mediated transactivity, whereas that of other ERR subtypes had no effect on the transactivity of ERα. Consistent with this finding, E2-stimulated proliferation of MCF-7 breast carcinoma cells and bcl-2 expression was significantly inhibited by expression of ERRβ. These results provide strong evidence for a suppressive effect of ERRβ on estrogen signaling through reduction of the intranuclear mobility of ERα. The findings further suggest a unique inhibitory role for ERRβ in estrogen-dependent cellular function such as cancer cell proliferation.
authors: From the Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan t-tanida@koto.kpu-m.ac.jp.
authors: Takashi
authors: T
authors: Tanida
authors: From the Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors: Ken Ichi
authors: KI
authors: Matsuda
authors: From the Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors: Shunji
authors: S
authors: Yamada
authors: From the Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors: Takashi
authors: T
authors: Hashimoto
authors: From the Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors: Mitsuhiro
authors: M
authors: Kawata
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D019556:COS Cells; D002277:Carcinoma / Q000378:metabolism; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000378:metabolism*; D017422:Sequence Analysis, DNA
chemical_list: C506487:ESR1 protein, human; C490918:ESRRB protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D011960:Receptors, Estrogen; D004958:Estradiol
keywords: Breast Cancer; Estrogen Receptor; Estrogen-related Receptor (ERR); Fluorescence Recovery after Photobleaching (FRAP); Fluorescence Resonance Energy Transfer (FRET); Live-cell Imaging; Transcription