Estrogen-related Receptor β Reduces the Subnuclear Mobility of Estrogen Receptor α and Suppresses Estrogen-dependent Cellular Function

Tanida, Takashi; Matsuda, Ken; Yamada, Shunji; Hashimoto, Takashi; Kawata, Mitsuhiro

doi:10.1074/jbc.m114.619098

Cited by 36 publications

(37 citation statements)

References 68 publications

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“…Prior studies have evaluated the subcellular localization of untagged and epitope-tagged ERRβ splice variants in breast cancer and other cell lines, and have consistently shown that exogenous ERRβsf is a nuclear protein [26, 38], which we also observe for the endogenous splice variant in MDA-MB-231 and HCC1806 cells. However, there are discrepancies in the reported subcellular localization of exogenous ERRβ2.…”

Section: Discussionmentioning

confidence: 55%

“…High levels of total ESRRB mRNA in primary breast tumors are associated with a reduction in cells in S phase and increased expression of estrogen receptor beta (ERβ) [37]. In exogenous expression studies, ERRβsf interacts with ER, alters the intranuclear localization of ER, and suppresses ER-mediated gene transcription in MCF7 cells [38]. Exogenous expression of ERRβ “long form” (a synonym for ERRβ2 used by some) in MCF7 cells leads to apoptosis and also shows an interaction with ER that is attenuated upon exposure to estradiol [39].…”

Section: Resultsmentioning

confidence: 99%

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Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

et al. 2016

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Breast cancer remains a leading cause of cancer-related death in women, and triple negative breast cancer (TNBC) lacks clinically actionable therapeutic targets. Death in mitosis is a tumor suppressive mechanism that occurs in cancer cells experiencing a defective M phase. The orphan estrogen-related receptor beta (ERRβ) is a key reprogramming factor in murine embryonic and induced pluripotent stem cells. In primates, ERRβ is alternatively spliced to produce several receptor isoforms. In cellular models of glioblastoma, short form (ERRβsf) and beta2 (ERRβ2) splice variants differentially regulate cell cycle progression in response to the synthetic agonist DY131, with ERRβ2 driving arrest in G2/M.The goals of the present study are to determine the cellular function(s) of ligand-activated ERRβ splice variants in breast cancer and evaluate the potential of DY131 to serve as an antimitotic agent, particularly in TNBC. DY131 inhibits growth in a diverse panel of breast cancer cell lines, causing cell death that involves the p38 stress kinase pathway and a bimodal cell cycle arrest. ERRβ2 facilitates the block in G2/M, and DY131 delays progression from prophase to anaphase. Finally, ERRβ2 localizes to centrosomes and DY131 causes mitotic spindle defects. Targeting ERRβ2 may therefore be a promising therapeutic strategy in breast cancer.

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Section: Discussionmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

et al. 2016

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“…Intranuclear dynamics are complex, affected by binding interactions, the presence of monomers vs dimers, flow, and inhomogeneity in space . Imaging studies of GFP‐tagged steroid hormone receptors, including the GR, mineralocorticoid receptor, estrogen receptor, and the androgen receptor have shown changes in intranuclear dynamics affected by a number of factors, such as ligand availability, transcriptional activity, and proteasomal activity . An earlier study of TRβ1 intranuclear mobility by FRAP noted that overexpression of SRC‐1, N‐CoR1, and HDAC did not affect TRβ1's intranuclear mobility; however, when factors retaining unliganded TRβ1 in the nucleus were studied, findings pointed towards a role of N‐CoR1 and RXR in maintaining the receptor in the nucleus .…”

Section: Discussionmentioning

confidence: 99%

Mediator subunit MED1 modulates intranuclear dynamics of the thyroid hormone receptor

Femia

Evans

Zhang

et al. 2019

J of Cellular Biochemistry

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The thyroid hormone receptors (TRs) mediate thyroid hormone (T3)‐dependent gene expression. The nuclear import and export signals that direct TR shuttling are well characterized, but little is known about factors modulating nuclear retention. We used fluorescence‐based nucleocytoplasmic scoring and fluorescence recovery after photobleaching in transfected cells to investigate whether Mediator subunits MED1 and MED13 play a role in nuclear retention of TR. When MED1 was overexpressed, there was a striking shift towards a greater nuclear localization of TRβ1 and the oncoprotein v‐ErbA, subtypes with cytosolic populations at steady‐state, and TRβ1 intranuclear mobility was reduced. For TRα1, there was no observable change in its predominantly nuclear distribution pattern or mobility. Consistent with a role for MED1 in nuclear retention, the cytosolic TRα1 and TRβ1 population were significantly greater in MED1−/− cells, compared with MED1+/+ cells. Exposure to T3 and epidermal growth factor, which induces MED1 phosphorylation, also altered TR intranuclear dynamics. Overexpression of miR‐208a, which downregulates MED13, led to a more cytosolic distribution of nuclear‐localized TRα1; however, overexpression of MED13 had no effect on TRβ1 localization. The known binding site of MED1 overlaps with a transactivation domain and nuclear export signal in helix 12 of TR's ligand‐binding domain (LBD). Coimmunoprecipitation assays demonstrated that TR's LBD interacts directly with exportins 5 and 7, suggesting that binding of exportins and MED1 to TR may be mutually exclusive. Collectively, our data provide evidence that MED1 promotes nuclear retention of TR, and highlight the dual functionality of helix 12 in TR transactivation and nuclear export.

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“…ESRRB (estrogen-related receptor beta) encodes a protein similar to the estrogen receptor and is believed to have an inhibitory effect on estrogen signaling 27 . Mutations in this gene have also been associated with hearing impairment and dental decay 35 .…”

Section: Discussionmentioning

confidence: 99%

Genetic and familial predisposition to rotator cuff disease: a systematic review

Dabija

Gao

Edwards

et al. 2017

Journal of Shoulder and Elbow Surgery

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Background Rotator cuff disease is a common disorder leading to shoulder pain and loss of function. Its etiology in atraumatic cases is uncertain and likely extends beyond repetitive micro-trauma or overuse. Our objective was to determine whether there is a genetic or familial predisposition to rotator cuff disease. Methods A literature search of PubMed and EMBASE databases identified 251 citations. After reviewing the titles, abstracts, and full articles, seven met our inclusion/exclusion criteria. Results Four studies assessed familial predisposition to rotator cuff disease. One of these demonstrated that siblings of an individual with a rotator cuff tear were more likely to develop a full-thickness tear and more likely to be symptomatic. A five-year follow-up showed that the relative risks were increased for the siblings to have a full-thickness tear, for a tear to progress in size, and for being symptomatic. Another study demonstrated that a significantly higher number of individuals with tears had family members with a history of tears or surgery than those without tears. The other three studies investigated whether a genetic predisposition to rotator cuff disease exists and found significant association of haplotypes in DEFB1, FGFR1, FGFR3, ESRRB, and FGF10, and two single nucleotide polymorphisms within SAP30BP and SASH1. Conclusion Prior studies provide preliminary evidence for genetic and familial predisposition to rotator cuff disease. However, there is a lack of large genome-wide studies that can provide more definitive information and guide early detection of individuals at risk, prophylactic rehabilitation, and potential gene therapies and regenerative medicine interventions. Level of Evidence Systematic Review

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Estrogen-related Receptor β Reduces the Subnuclear Mobility of Estrogen Receptor α and Suppresses Estrogen-dependent Cellular Function

Cited by 36 publications

References 68 publications

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

Mediator subunit MED1 modulates intranuclear dynamics of the thyroid hormone receptor

Genetic and familial predisposition to rotator cuff disease: a systematic review

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