Down but not out? A novel protein isoform of the estrogen receptor alpha is expressed in the estrogen receptor alpha knockout mouse

Koš, Martin; Denger, Stefanie; Reid, George; Korach, Kenneth S.; Gannon, Frank

doi:10.1677/jme.0.0290281

Cited by 74 publications

(64 citation statements)

References 37 publications

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“…The lack of well delineated bands in lanes containing tissue proteins, with clear single bands in lanes containing recombinant proteins, is likely due to heterogeneity in ER types within tissues. This is consistent with the fact that either ER␣ or ER␤ could bind the ERE and that variants of ERs have been demonstrated in nonimmune tissues previously (24,25). Together the alteration in cytokine production during in vitro estriol treatment of immune cells and the binding of splenic protein to ERE indicated that functional ERs are expressed in murine secondary lymphoid tissues.…”

Section: Functional Er Are Present In Peripheral Immune Tissuessupporting

confidence: 86%

“…Furthermore, expression of ER␣ at the protein level in the peripheral immune system has remained poorly characterized since Western blot data were negative for specific bands of the correct size (31) while flow cytometry of immune cells was positive (29,32,33). Together these previous reports raised the question of whether the classic ER␣, vs another ER variant (24,25), was detected in immune cells by flow cytometry. Thus, we characterized ER␣ expression in secondary lymphoid tissues of mice at the RNA level by both nested RT-PCR and sequencing and at the protein level by Western blot using both Ab and ligand binding.…”

Section: Er␣ Expression At the Rna And Protein Levelsmentioning

confidence: 99%

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Estrogen Receptor α Mediates Estrogen’s Immune Protection in Autoimmune Disease

Liu

Loo

Palaszynski

et al. 2003

The Journal of Immunology

142

124

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Estrogens are known to influence a variety of autoimmune diseases, but it is not known whether their actions are mediated through classic estrogen receptor α (ERα). The presence of a functional ER was demonstrated in secondary lymphoid tissues, then ERα expression was shown at both the RNA and protein levels in these tissues. Use of ERα knockout mice revealed that both the estrogen-induced disease protection and the estrogen-induced reduction in proinflammatory cytokines were dependent upon ERα in the prototypic Th1-mediated autoimmune disease experimental autoimmune encephalomyelitis. These findings are central to the design of selective ER modifiers which aim to target biologic responses in specific organ systems.

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Section: Functional Er Are Present In Peripheral Immune Tissuessupporting

confidence: 86%

Section: Er␣ Expression At the Rna And Protein Levelsmentioning

confidence: 99%

Estrogen Receptor α Mediates Estrogen’s Immune Protection in Autoimmune Disease

Liu

Loo

Palaszynski

et al. 2003

The Journal of Immunology

142

124

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“…The explanation of this apparent discrepancy resides most likely in the recently characterized phenotypic difference between these two mutant strains. Although the expression of the full-length 66 kDa isoform of ER␣ (p66) is abolished in ER␣-Neo Ϫ/Ϫ mice, two others splice variants lacking the AF-1 transactivator domain have been identified (p55, p46) that still possess a residual estrogen-dependent transcriptional activity (22)(23)(24). In contrast, in the mouse model of complete inactivation of ER␣ used in the present study (13,22), E 2 , even in high amounts, failed to promote DC differentiation from BM progenitors, demonstrating that ER␤ signaling could not compensate for the lack of ER␣.…”

Section: Cd11bmentioning

confidence: 99%

Estrogen Receptor α, but Not β, Is Required for Optimal Dendritic Cell Differentiation and CD40-Induced Cytokine Production

Douin‐Echinard

Laffont

Seillet

et al. 2008

The Journal of Immunology

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Dendritic cells (DC) are critical actors in the initiation of primary immune responses and regulation of self-tolerance. The steroid sex hormone 17β-estradiol (E2) has been shown to promote the differentiation of DCs from bone marrow (BM) precursors in vitro. However, the estrogen receptor (ER) involved in this effect has not yet been characterized. Using recently generated ERα- or ERβ-deficient mice, we investigated the role of ER isotypes in DC differentiation and acquisition of effector functions. We report that estrogen-dependent activation of ERα, but not ERβ, is required for normal DC development from BM precursors cultured with GM-CSF. We show that reduced numbers of DCs were generated in the absence of ERα activation and provide evidence for a cell-autonomous function of ERα signaling in DC differentiation. ERα-deficient DCs were phenotypically and functionally distinct from wild-type DCs generated in the presence of estrogens. In response to microbial components, ERα-deficient DCs failed to up-regulate MHC class II and CD86 molecules, which could account for their reduced capacity to prime naive CD4+ T lymphocytes. Although they retained the ability to express CD40 and to produce proinflammatory cytokines (e.g., IL-12, IL-6) upon TLR engagement, ERα-deficient DCs were defective in their ability to secrete such cytokines in response to CD40–CD40L interactions. Taken together, these results provide the first genetic evidence that ERα is the main receptor regulating estrogen-dependent DC differentiation in vitro and acquisition of their effector functions.

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“…The E1 transcript encodes for a chimeric ER-␣ protein in which amino acids 92-155 of the B domain of the wild type ER-␣ protein are replaced with 7 amino acids from a small portion of the neomycin insert. This eliminates or greatly diminishes AF-1 function but not DNA or ligand binding AF-2 transactivation function (26). Although this mutant isoform of ER-␣ does promote E 2-dependent transcriptional activity, it does so at a much lower activity compared with full length ER␣66 (26,27).…”

mentioning

confidence: 97%

“…This eliminates or greatly diminishes AF-1 function but not DNA or ligand binding AF-2 transactivation function (26). Although this mutant isoform of ER-␣ does promote E 2-dependent transcriptional activity, it does so at a much lower activity compared with full length ER␣66 (26,27). Data obtained in the present study demonstrate that nonovariectomized ␣ERKO female mice are more sensitive to injurious effects of RSLϩI/R than their wt counterparts such that survival decreased from 100% in wt mice to only 40% in the ␣ERKO mice (Fig.…”

mentioning

confidence: 99%

Estrogen Receptor-α, Sexual Dimorphism and Reduced-Size Liver Ischemia and Reperfusion Injury in Mice

Harada¹,

Bharwani

Pavlick³

et al. 2004

Pediatr Res

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Estrogen (E 2 ) exerts its effect on target organs principally by interacting with specific estrogen receptors (ER) such as ER-␣ or ER-␤. The role that these E 2 receptors play in mediating the protective effects observed in RSLϩI/R induced injury remains to be defined. To study the role of ER-␣, we anesthetized female and male wild type (wt; C57Bl/6) and ER-␣-deficient (␣ERKO) mice and subjected them to 70% liver ischemia for 45 min followed by resection of the remaining 30% nonischemic lobes and reperfusion of the ischemic tissue. For some experiments, wt and ␣ERKO male mice were injected with E 2 . Survival was monitored on a daily basis while liver injury was assessed by quantifying serum alanine aminotransferase (ALT) levels and histopathology. Hepatic eNOS mRNA levels were evaluated using semi-quantitative RT-PCR. Our data showed that untreated females or males treated with E 2 survived RSLϩI/R surgery indefinitely whereas all male mice given vehicle died within 3-5 days following surgery. This protective effect was diminished in ␣ERKO female mice such that only 40% of ␣ERKO females survived 7 d following RSLϩI/R. Furthermore, liver injury was significantly higher in ␣ERKO females compared with their wt counterparts and similar to those seen in wild type males and ␣ERKO males. The protective effect observed in wild type females or E 2 treated males correlated well with increases in hepatic eNOS message whereas both male and female ␣ERKO mice exhibited significantly lower levels of eNOS mRNA. We conclude that this protection may in part be due to the E 2 /ER-␣-mediated activation of eNOS. Abbreviations NO, nitric oxide ROS, reactive oxygen species eNOS, endothelial nitric oxide synthase ␣ERKO, estrogen receptor alpha knockout I/R, ischemia/reperfusion wt, wild type RSL؉I/R, reduced-size liver with ischemia and reperfusion injury Hepatic resection with concomitant periods of ischemia and reperfusion (I/R) is a common occurrence in certain surgical procedures such as split liver or living donor transplantation (1, 2). These types of transplantations represent surgical alternatives to whole liver transplantation and are being applied to expand the depleted donor organ pool (1, 2) as well as provide children with size-matched livers. Indeed, the high death rate (7% to 15%) in pediatric liver patients waiting for sizematched cadaveric liver donors (3) has led to the utilization of these types of innovative surgical techniques such as living related transplants (LRT), the reduced size (cut-down) liver grafts and split grafts. These technical advances have led to the reduction in the waiting list mortality (4), however, the success has been fraught with difficulties, medical as well as ethical. For example, the hepatocellular injury induced by I/R is known to impair liver regeneration and may lead to primary graft dysfunction and failure (2, 5, 6). The mechanisms by which RSLϩI/R promotes liver injury are not clear at the present time. However, numerous experimental studies using warm, full-size liver I/R indicate...

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Down but not out? A novel protein isoform of the estrogen receptor alpha is expressed in the estrogen receptor alpha knockout mouse

Cited by 74 publications

References 37 publications

Estrogen Receptor α Mediates Estrogen’s Immune Protection in Autoimmune Disease

Estrogen Receptor α Mediates Estrogen’s Immune Protection in Autoimmune Disease

Estrogen Receptor α, but Not β, Is Required for Optimal Dendritic Cell Differentiation and CD40-Induced Cytokine Production

Estrogen Receptor-α, Sexual Dimorphism and Reduced-Size Liver Ischemia and Reperfusion Injury in Mice

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