Estrogen and the selective estrogen receptor modulator (SERM) protection against cell death in estrogen receptor alpha and beta expressing U2OS cells

Kallio, Anu; Guo, Tao; Lamminen, Elisa; Seppänen, Jani; Kangas, Lauri; Väänänen, H. Kalervo; Härkönen, Pirkko

doi:10.1016/j.mce.2008.03.005

Cited by 37 publications

(32 citation statements)

References 75 publications

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“…E2 (10 -8 ∼10 -10 M) has similar ability to stimulate the induction of collagenase-3 mRNA in UMR 106-01 cells (Partridge et al, 2000). Transfection with either ERα or ERβ causes U2OS cell sensitivity to E2 (Lima et al, 2004;Kallio et al, 2008). We previously reported that E2 (1 μM) does not positively regulate cell proliferation in MC-3T3-E1 cells (Guo et al, 2007).…”

Section: Discussionmentioning

confidence: 91%

Transcriptional activation of insulin-like growth factor binding protein 6 by 17β-estradiol in SaOS-2 cells

et al. 2009

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Osteoblasts can synthesize the insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs), which may either enhance or attenuate IGF-stimulated bone cell proliferation. Since estrogen induced osteoblastic differentiation and proliferation through an estrogen-responsive gene in target cells, we investigated the effects of estrogen on IGFBP-6 expression in the human osteoblastic-like cell line SaOS-2. Expressions of IGFBP-6 protein and mRNA increased 2.8 and 2-fold, respectively, in the presence of 17-β-estradiol (E2) (0.01 to 1 μM) and estrogen receptor (ER) in SaOS-2 cells. On the other hand, E2 induced a 2-fold increase in SaOS-2 cell proliferation. To identify genomic sequences associated with estrogen responsiveness, the 5'-promoter region (-44 to +118) of the IGFBP-6 gene was cloned into a chloramphenicol acetyltransferase (CAT) reporter vector. E2 induced a 3-fold increase in CAT activity in SaOS-2 cells transiently transfected with this construct. Identification of the estrogen-responsive element (ERE) [5'-CCTTCA CCTG-3'] (-9 to +1) in this IGFBP-6 gene promoter region was confirmed using electromobility shift assays and deletion analysis. This functional ERE was important for E2-induced trans-activation of the IGFBP-6 gene.These results demonstrate that E2 exhibits a positive effect on IGFBP-6 gene transcription through estrogen-liganded ER binding to the functional ERE in the IGFBP-6 gene promoter in SaOS-2 cells.

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Section: Discussionmentioning

confidence: 91%

Transcriptional activation of insulin-like growth factor binding protein 6 by 17β-estradiol in SaOS-2 cells

et al. 2009

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“…First, the influence of FC on ERα transcriptional activity was tested, as well as the role of the F-domain C-terminal tip therein. To rule out any influence of endogenous receptor, we made use of ERα-negative human osteosarcoma cell line U2OS, a wellannotated model system for ERα action (30). ERα-mediated estrogen response element-luciferase reporter (ERE-luc) expression was measured in U2OS cells cotransfected with ERα wild type (ERα-WT) and two C-terminal mutants: ERα-T 594 A and ERα-Δ4, a construct lacking the last four amino acids.…”

Section: Yellow) (E) Perα (Green) Interaction With 14-3-3σ (Gray) (F)mentioning

confidence: 99%

Interaction of 14-3-3 proteins with the Estrogen Receptor Alpha F domain provides a drug target interface

Leeuwen

Pereira

Flach

et al. 2013

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

126

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Estrogen receptor alpha (ERα) is involved in numerous physiological and pathological processes, including breast cancer. Breast cancer therapy is therefore currently directed at inhibiting the transcriptional potency of ERα, either by blocking estrogen production through aromatase inhibitors or antiestrogens that compete for hormone binding. Due to resistance, new treatment modalities are needed and as ERα dimerization is essential for its activity, interference with receptor dimerization offers a new opportunity to exploit in drug design. Here we describe a unique mechanism of how ERα dimerization is negatively controlled by interaction with 14-3-3 proteins at the extreme C terminus of the receptor. Moreover, the small-molecule fusicoccin (FC) stabilizes this ERα/14-3-3 interaction. Cocrystallization of the trimeric ERα/ 14-3-3/FC complex provides the structural basis for this stabilization and shows the importance of phosphorylation of the penultimate Threonine (ERα-T 594 ) for high-affinity interaction. We confirm that T 594 is a distinct ERα phosphorylation site in the breast cancer cell line MCF-7 using a phospho-T 594 -specific antibody and by mass spectrometry. In line with its ERα/14-3-3 interaction stabilizing effect, fusicoccin reduces the estradiol-stimulated ERα dimerization, inhibits ERα/chromatin interactions and downstream gene expression, resulting in decreased cell proliferation. Herewith, a unique functional phosphosite and an alternative regulation mechanism of ERα are provided, together with a small molecule that selectively targets this ERα/14-3-3 interface.T he estrogen receptor alpha (ERα) is a ligand-dependent transcription factor and the driving force of cell proliferation in 75% of all breast cancers. Current therapeutic strategies to treat these tumors rely on selective ER modulators (SERMs), like tamoxifen (TAM) (1) or aromatase inhibitors (AIs) that block estradiol synthesis (2). Although the benefits of treating hormone-sensitive breast cancers with SERMs and AIs are evident, resistance to treatment is commonly observed (3, 4). To overcome resistance, selective ERα down-regulators (SERDs) can for instance be applied that inhibit ERα signaling through receptor degradation (5, 6). Approaches that target the ERα/ DNA or ERα/cofactor interactions are explored as well (5, 7), but other essential steps in the ERα activation cascade are currently unexploited in drug design, also due to a lack of molecular understanding of the processes at hand.One such step that is crucial for many aspects of ERα functioning is ligand-driven receptor dimerization (8, 9). 17β-Estradiol (E2) association with the ERα ligand binding domain (LBD) drives large conformational changes (10) resulting in ERα dissociation from chaperones (11, 12), unmasking of domains for receptor dimerization, and DNA binding (13,14). Whereas the LBD contains the main dimerization domain (15), the extreme C-terminal domain of the receptor (F domain) imposes a restraint on dimerization (15, 16), although the regulation of this remain...

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“…Although the protective effect of raloxifene on bone mass is known, less is known regarding its action mechanism. It has been suggested that raloxifene prevents osteoblast death and inhibits oxidative stress-induced endothelial cell apoptosis (16,36). These effects may operate through a receptor-independent mechanism related to the antioxidant activity of SERMs (36).…”

Section: Raloxifene Effects On Avcmentioning

confidence: 99%

“…It is a mixed estrogen receptor agonist and antagonist, which has been shown to reduce cardiovascular events in women at high risk for coronary artery disease (5). Although the mechanism of the raloxifene effect on atherosclerosis is not completely understood, it has been shown to reduce both osteoblast cell apoptosis and oxidative stress damage (16,36). However, its role in valvular calcification is still unknown.…”

mentioning

confidence: 99%

Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure

Shuvy

Abedat

Beeri

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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failure is associated with aortic valve calcification. Using our rat model of uremiainduced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in that disease. We also explored the effects of raloxifene, an estrogen receptor modulator, on valvular calcification. Gene array analysis was performed in aortic valves obtained from three groups of rats (n ϭ 7 rats/group): calcified valves obtained from rats fed with uremic diet, valves after calcification resolution following diet cessation, and control. In addition, four groups of rats (n ϭ 10 rats/group) were used to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet that also received daily raloxifene. Evaluation included imaging, histology, and antigen expression analysis. Gene array results showed that the majority of the altered expressed genes were in diet group valves. Most apoptosisrelated genes were changed in a proapoptotic direction in calcified valves. Apoptosis and decreases in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of survival pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. In conclusion, downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.growth arrest-specific 6; uremia CARDIOVASCULAR CALCIFICATION is one of the highest causes of morbidities and mortalities in patients with end-stage renal disease. These patients develop aortic valve calcification (AVC) and coronary calcification at an accelerated rate. Associated with this cardiovascular calcification are increased rates of myocardial infarctions and valvular heart disease. The pathogenesis of AVC in renal failure (RF) is not fully elucidated. It has been suggested that the process involves active osteoblast transformation of valve tissue, which results in increased formation of bone matrix (4, 25). Most of the data regarding the pathogenesis of AVC were obtained from animal models based on various components of the metabolic syndrome, emphasizing the role of atherogenesis in AVC (26, 37). In patients with RF, AVC and aortic stenosis are common and progress especially rapidly (18). The prevalence and extent of AVC in this population is poorly explained by traditional cardiovascular risk factors; abnormalities of mineral metabolism are likely to contribute to its development and progression. Current models of RF and accelerated calcification have demonstrated that calcium phosphate metabolism is critical for disease development (13), and inhibitors of calcification (fetuin A) are important in its prevention...

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Estrogen and the selective estrogen receptor modulator (SERM) protection against cell death in estrogen receptor alpha and beta expressing U2OS cells

Cited by 37 publications

References 75 publications

Transcriptional activation of insulin-like growth factor binding protein 6 by 17β-estradiol in SaOS-2 cells

Transcriptional activation of insulin-like growth factor binding protein 6 by 17β-estradiol in SaOS-2 cells

Interaction of 14-3-3 proteins with the Estrogen Receptor Alpha F domain provides a drug target interface

Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure

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