Steroid hormone receptor expression and action in bone

Bland, Rosemary

doi:10.1042/cs0980217

Cited by 105 publications

(82 citation statements)

References 204 publications

(267 reference statements)

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“…Localization studies indicate that ER and Rho GDI are found in distinct subcellular compartments, with Rho GDI residing in the cytoplasm, whereas ER is confined to the nucleus. 3 In addition, GST-Rho GDI is unable to associate with estradiol-bound ER, although it is capable of binding Rho A in vitro. 3 While Brx and Rho GTPases may modulate ER activity through distinct mechanisms, the identification of different components in the Rho signaling pathway as modulators of ER transactivation underscores their importance in receptor regulation.…”

Section: Figmentioning

confidence: 99%

“…Although the mechanism of this increased ER transcriptional activation remains to be elucidated, it probably involves phosphorylation-dependent cofactor recruitment (68). Thus, Ras acts as a positive regulator of ER transcriptional enhancement (67), 3 whereas Rho GTPases suppress receptor transactivation. We speculate that the opposing actions of Ras and Rho GTPases on ER-mediated transcriptional activation provide a means of fine tuning the ER transcriptional response to changes in the extracellular environment.…”

Section: Figmentioning

confidence: 99%

“…Activation of ER is responsible for female sexual development and maintenance of bone density (2,3). In addition, ER plays a critical role in the development and progression of breast cancer by regulating genes and signaling pathways involved in cellular proliferation (4).…”

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confidence: 99%

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Rho GTPases as Modulators of the Estrogen Receptor Transcriptional Response

Knoblauch

Garabedian

2001

Journal of Biological Chemistry

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The estrogen receptor ␣ (ER) is a ligand-dependent transcription factor that plays a critical role in the development and progression of breast cancer, in part, by regulating target genes involved in cellular proliferation. To identify novel components that affect the ER transcriptional response, we performed a genetic screen in yeast and identified RDI1, a Rho guanine nucleotide dissociation inhibitor (Rho GDI), as a positive regulator of ER transactivation. Overexpression of the human homologue of RDI1, Rho GDI␣, increases ER␣, ER␤, androgen receptor, and glucocorticoid receptor transcriptional activation in mammalian cells but not activation by the unrelated transcription factors serum response factor and Sp1. In contrast, expression of constitutively active forms of RhoA, Rac1, and Cdc42 decrease ER transcriptional activity, suggesting that Rho GDI increases ER transactivation by antagonizing Rho function. Inhibition of RhoA by expression of either the Clostridium botulinum C3 transferase or a dominant negative RhoA resulted in enhanced ER transcriptional activation, thus phenocopying the effect of Rho GDI expression on ER transactivation. Together, these findings establish the Rho GTPases as important modulators of ER transcriptional activation. Since Rho GTPases regulate actin polymerization, our findings suggest a link between the major regulators of cellular architecture and steroid receptor transcriptional response. The estrogen receptor ␣ (ER)1 is a ligand-dependent transcription factor that transduces the estrogen signal (1). Activation of ER is responsible for female sexual development and maintenance of bone density (2, 3). In addition, ER plays a critical role in the development and progression of breast cancer by regulating genes and signaling pathways involved in cellular proliferation (4). Regulation of gene expression by the ER requires the coordinate activity of ligand binding, phosphorylation, and cofactor interactions, with particular combinations probably resulting in the tissue-specific responses elicited by the receptor (5-7). However, the extracellular cues and intracellular signaling pathways modulating these components and regulating ER transcriptional activation are not fully understood.To identify novel proteins that modulate ER transcriptional activation, we have carried out a genetic screen in the yeast Saccharomyces cerevisiae. The ability of the human ER to function within yeast allows a wide variety of genetic approaches to be taken toward further defining the mechanism of ER transcriptional activation given the ease of genetic manipulation and simplicity of gene identification in yeast. In addition, with the large number of orthologous proteins carrying out the same biological functions in both S. cerevisiae and metazoans (8 -10), it is likely that the yeast factors affecting ER transactivation will have mammalian counterparts, which can be examined in vertebrate systems.The genetic approach we have used to identify factors that affect ER transcriptional activation is dosage su...

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Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Rho GTPases as Modulators of the Estrogen Receptor Transcriptional Response

Knoblauch

Garabedian

2001

Journal of Biological Chemistry

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“…teroid sex hormones are essential for normal skeletal development and maintenance of healthy bone remodeling during adult life (1,2). Sex hormone status reflects bone mass, such that hormonal deficiency is well known to lead to progressive bone loss (3).…”

mentioning

confidence: 99%

Suppressive function of androgen receptor in bone resorption

Kawano

Satō

Yamada

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

292

210

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As locally converted estrogen from testicular testosterone contributes to apparent androgen activity, the physiological significance of androgen receptor (AR) function in the beneficial effects of androgens on skeletal tissues has remained unclear. We show here that inactivation of AR in mice using a Cre-loxP system-mediated gene-targeting technique caused bone loss in males but not in females. Histomorphometric analyses of 8-week-old male AR knockout (ARKO) mice showed high bone turnover with increased bone resorption that resulted in reduced trabecular and cortical bone mass without affecting bone shape. Bone loss in orchidectomized male ARKO mice was only partially prevented by treatment with aromatizable testosterone. Analysis of primary osteoblasts and osteoclasts from ARKO mice revealed that AR function was required for the suppressive effects of androgens on osteoclastogenesis supporting activity of osteoblasts but not on osteoclasts. Furthermore, expression of the receptor activator of NF-B ligand (RANKL) gene, which encodes a major osteoclastogenesis inducer, was found to be up-regulated in osteoblasts from ARdeficient mice. Our results indicate that AR function is indispensable for male-type bone formation and remodeling.

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“…ERa and ERb are each expressed in osteoblasts and osteoclasts (Lim et al, 1999;Bland, 2000;Bord et al, 2001). The potential roles of the 2 ER isoforms in bone homeostasis are under intense investigation.…”

Section: Introductionmentioning

confidence: 99%

Relationship between estrogen receptor 1 gene polymorphisms and postmenopausal osteoporosis of the spine in Chinese women

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The purpose of this study was to evaluate single nucleotide polymorphism (SNP) variants of the estrogen receptor 1 gene (ESR1) at rs2234693 and rs9340799, as well as to investigate the relationship between ESR gene polymorphisms and postmenopausal osteoporosis (OP) of the spine in Chinese women. We recruited 198 postmenopausal women with OP and 276 healthy women between May 2012 and September 2015 in Zhongshan Hospital. Dual energy x-ray absorptiometry was used to measure the bone mineral density (BMD) of the lumbar vertebrae in all subjects. In addition, PCR-restriction fragment length polymorphism based analysis was conducted to identify the genotypes of ESR1. The distribution of ESR1 in the osteoporosis group and the control group was determined; the relationship between ESR polymorphisms and BMD was analyzed. The distributions of BMD were: TT < TC < CC, GG < AG < AA. The TT, TTGG, and TCGG genotypes were found to be lower as compared to the other genotypes. Stratified analysis suggested that the TT genotype and the combined genotypes TTGG and TCGG were significantly higher in the OP group as compared to the control group (P < 0.01). Therefore, ESR1 polymorphisms at rs2234693 and rs9340799 may be associated with OP, and could be used as markers to screen those with high risks to postmenopausal OP in Chinese women.

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Steroid hormone receptor expression and action in bone

Cited by 105 publications

References 204 publications

Rho GTPases as Modulators of the Estrogen Receptor Transcriptional Response

Rho GTPases as Modulators of the Estrogen Receptor Transcriptional Response

Suppressive function of androgen receptor in bone resorption

Relationship between estrogen receptor 1 gene polymorphisms and postmenopausal osteoporosis of the spine in Chinese women

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