The oestrogen receptor regulates NFκB and AP-1 activity in a cell-specific manner

Cerillo, Georgia; Rees, Amanda; Manchanda, Nina; Reilly, Christopher F.; Brogan, Iain J.; White, Anne; Needham, Maurice

doi:10.1016/s0960-0760(98)00078-8

Cited by 108 publications

(60 citation statements)

References 51 publications

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“…In agreement with our findings, overexpression of SRC1 has also been reported to have no effect on modulating ER-dependent down-regulation of NF-B in either HeLa or HEK-293 cells (68). Similar conclusions were drawn for AP1 transrepression by the thyroid hormone receptor, because the integrity of AF2 in the thyroid hormone receptor did not alter the ability of the receptor to inhibit AP1 (69).…”

Section: Right Panel)supporting

confidence: 92%

Mutations in the Estrogen Receptor Ligand Binding Domain Discriminate between Hormone-dependent Transactivation and Transrepression

Valentine

Kalkhoven

White

et al. 2000

Journal of Biological Chemistry

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The estrogen receptor (ER) suppresses transcriptional activity of the RelA subunit of nuclear factor-B in a hormone-dependent manner by a mechanism involving both the receptor DNA binding domain and ligand binding domain (LBD). In this study we examine the role of the ER LBD in mediating ligand-dependent RelA transrepression. Both ER␣ and ER␤ inhibit RelA in response to 17␤-estradiol but not in the presence of antihormones. We have identified residues within the ER␣ LBD that are responsible for receptor dimerization and show that dimerization is necessary for transactivation and transrepression. Moreover we have generated mutant receptors that have lost their ability to inhibit RelA but retain their capacity to stimulate transcription and conversely mutants that are transcriptionally defective but capable of antagonizing RelA. Overexpression of p160 and cAMP-response element-binding protein-binding protein/p300 co-activators failed to relieve repression of RelA, which is consistent with the demonstration that RelA inhibition can occur independently of these co-activators. These findings suggest it is unlikely that sequestration of these cofactors required for ER transcriptional activation can account for hormone-dependent antagonism of RelA. The identification of ER mutants that discriminate between transactivation and transrepression implies that distinct surfaces within the LBD are involved in mediating these two receptor functions.The pleiotropic effects of estrogens are mediated by estrogen receptors (ERs), 1 which function as hormone-activated transcription factors regulating the expression of a variety of estrogen-responsive genes. In common with other members of the nuclear receptor (NR) superfamily, ER contains three functional domains, an N-terminal region with a hormone-independent activation function (AF1), a conserved central DNA binding domain (DBD), and a C-terminal ligand binding domain (LBD), which is responsible for high affinity ligand binding, dimerization, and hormone-dependent activation (AF2) (1-3). There are two forms of ER, ER␣, and ER␤, which share a high degree of homology in their DBD and LBD but contain divergent N-terminal domains (4, 5). In response to hormone binding, ER homodimers contact estrogen response elements (ERE) located within the regulatory sequences of target genes, resulting in the recruitment of co-activator proteins and consequent initiation of gene transcription (6, 7). Elucidation of the crystal structure of ER␣ and ER␤ LBD has revealed that they share a common modular structure with the LBD of related NRs, which can be divided into 12 discrete helices (see Refs. 8 -11, and the references therein). Comparison of these unliganded and liganded crystal structures suggests that upon ligand binding the LBD undergoes a conformational change whereby the C-terminal helix (H12 in ER) is realigned over the ligand binding pocket and in ER is packed against H3, H5/6, and H11 (8 -11). The activity of ER␣ AF2 is dependent on the integrity of a hydrophobic interaction surface gen...

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Section: Right Panel)supporting

confidence: 92%

Mutations in the Estrogen Receptor Ligand Binding Domain Discriminate between Hormone-dependent Transactivation and Transrepression

Valentine

Kalkhoven

White

et al. 2000

Journal of Biological Chemistry

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“…The functional interaction, or cross-talk, between ER and NF-kB has been suggested to play a key role in estrogen's ability to prevent age-related conditions and tumorigenesis in vivo (Dijsselbloem et al, 2004). Pro-or anti-inflammatory roles of estrogens on NF-kB-dependent gene expression have been shown to strongly depend on cell type (signaling circuitries, cofactor dynamics, repertoire of ER isoforms and chromatin promoter context) (Cerillo et al, 1998;Maret et al, 1999;Wissink et al, 2001;Cheung et al, 2003;Cutolo et al, 2003;Bhat-Nakshatri et al, 2004;Kalaitzidis and Gilmore, 2005;Vanden Berghe et al, 2006a) or ligand metabolism (Cutolo et al, 2004). Of special note, loss of ER function has been associated with constitutive NF-kB activity and hyperactive MAPK, because of constitutive secretion of cytokine and growth factors, which ultimately culminates in aggressive, metastatic, hormone-resistant cancers (Ali and Coombes, 2002;Pratt et al, 2003;Lu et al, 2004).…”

Section: Cross-talk Between Nf-jb and The Ermentioning

confidence: 99%

Cross-talk between nuclear receptors and nuclear factor κB

2006

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A variety of studies have shown that some activated nuclear receptors (NRs), especially the glucorticoid receptor, the estrogen receptor and peroxisome proliferator-activated receptor, can inhibit the activity of the transcription factor nuclear factor jB (NF-jB), which plays a key role in the control of genes involved in inflammation, cell proliferation and apoptosis. This review describes the molecular mechanisms of cross-talk between NRs and NF-jB and the biological relevance of this crosstalk. The importance and mechanistic aspects of selective NR modulation are discussed. Also included are future research prospects, which will lead to a new era in the field of NR research with the aim of specifically inhibiting NF-jB-driven gene expression for anti-inflammatory, anti-tumor and immune-modulatory purposes.

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“…Several previous reports have demonstrated that fulllength ERa can inhibit NF-kB-induced transactivation in an estrogen-dependent manner (Ray et al, 1994;Stein and Yang, 1995;Ray et al, 1997;Cerillo et al, 1998;Valentine et al, 2000;Evans et al, 2001;Sharma et al, 2001;Tzagarakis-Foster et al, 2002), but the mechanism by which this inhibition occurs is unclear. However, two studies have reported that ERa can bind preferentially to REL, as compared to other NF-kB subunits.…”

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confidence: 99%

Characterization of a human REL-estrogen receptor fusion protein with a reverse conditional transforming activity in chicken spleen cells

Kalaitzidis

Sulak

et al. 2004

Oncogene

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Overexpression of the human REL transcription factor can malignantly transform chicken spleen cells in vitro. In this report, we have created and characterized a cDNA encoding a chimeric protein (RELD424-490-ER) in which sequences of a highly transforming REL mutant (RELD424-490) are fused to the ligand-binding domain of the human estrogen receptor (ER). Surprisingly, RELD424-490-ER is constitutively nuclear in A293 cells, and RELD424-490-ER activates transcription in the absence, but not in the presence, of estrogen in jB-site reporter gene assays. Furthermore, RELD424-490-ER transforms chicken spleen cells in the absence of estrogen, but the addition of estrogen blocks the ability of RELD424-490-ER-transformed cells to form colonies in soft agar, even though estrogen induces increased nuclear translocation of RELD424-490-ER in these cells. ERa can also inhibit REL-dependent transactivation in trans in an estrogen-dependent manner, and ERa can interact with REL in vitro. Thus, the RELD424-490-ER fusion protein shows an unusual, reverse hormone regulation, in that its most prominent biological activities (transformation and transactivation) are inhibited by estrogen, probably due to an estrogen-induced interaction between the ER sequences and sequences in the Rel homology domain. Nevertheless, these results indicate that the continual activity of REL is required to sustain the transformed state of chicken spleen cells in culture, suggesting that direct and specific inhibitors of REL may have therapeutic efficacy in certain human lymphoid cancers.

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The oestrogen receptor regulates NFκB and AP-1 activity in a cell-specific manner

Cited by 108 publications

References 51 publications

Mutations in the Estrogen Receptor Ligand Binding Domain Discriminate between Hormone-dependent Transactivation and Transrepression

Mutations in the Estrogen Receptor Ligand Binding Domain Discriminate between Hormone-dependent Transactivation and Transrepression

Cross-talk between nuclear receptors and nuclear factor κB

Characterization of a human REL-estrogen receptor fusion protein with a reverse conditional transforming activity in chicken spleen cells

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