Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily

Oñate, Sergio A.; Tsai, Sophia Y.; Tsai, Ming‐Jer; O’Malley, Bert W.

doi:10.1126/science.270.5240.1354

Cited by 2,214 publications

(1,415 citation statements)

References 23 publications

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“…Since this breast cancer cDNA encoded a nuclear receptor-binding auxiliary protein (Segars et al, 1993), we called the gene brx. Overlapping cDNA clones were consistent with a 5.3 kilobase cDNA encoding a 1428 amino acid protein with a 168 kilodalton predicted molecular mass distinct from proteins reported to bind nuclear hormone receptors (Cavailles et al, 1994(Cavailles et al, , 1995Halachmi et al, 1994;Jacq et al, 1994;Chen and Evans, 1995;Horlein et al, 1995;Onate et al, 1995;Le Douarin et al, 1995;Baniahmad et al, 1995).…”

Section: Identi®cation and Cloning Of Brx Cdnasupporting

confidence: 54%

“…For example, gene activation by nuclear hormone receptors (NHRs) has recently been shown to include additional proteins that associate directly with receptors, including the estrogen receptor (see : Horwitz et al, 1996;Katzenellenbogen et al, 1996). Biochemical and interactive cloning methods have led to isolation of 120 (Le Douarin et al, 1995), 125 (Onate et al, 1995), 140 (Cavailles et al, 1994(Cavailles et al, , 1995Halachmi et al, 1994), 160 (Halachmi et al, 1994;Cavailles et al, 1994), 168 (Chen and Evans, 1995) and 270 (Horlein et al, 1995) kDa proteins shown to associate with ligand-bound NHRs and function as positive (co-activators) or negative (corepressors) of nuclear receptor action by modulating interaction with the basal transcription complex. In addition, CBP (and related protein p300) has been described as a`co-integrator' of hormone receptor function through interaction with the nuclear receptor binding protein p160, TFIIB, and Jun/Fos (Kamei et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

et al. 1998

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Regulation of gene activation by the estrogen receptor (ER) is complex and involves co-regulatory proteins, oncoproteins (such as Fos and Jun), and phosphorylation signaling pathways. Here we report the cloning and initial characterization of a novel protein, Brx, that contains a region of identity to the oncogenic Rhoguanine nucleotide exchange (Rho-GEF) protein Lbc, and a unique region capable of binding to nuclear hormone receptors, including the ER. Western and immunohistochemistry studies showed Brx to be expressed in estrogen-responsive reproductive tissues, including breast ductal epithelium. Brx bound speci®cally to the ER via an interaction that required distinct regions of ER and Brx. Furthermore, overexpression of Brx in transfection experiments using an estrogenresponsive reporter revealed that Brx augmented gene activation by the ER in an element-speci®c and liganddependent manner. Moreover, activation of ER by Brx could be speci®cally inhibited by a dominant-negative mutant of Cdc42Hs, but not by dominant negative mutants of RhoA or Rac1. Taken together, these data suggest that Brx represents a novel modular protein that may integrate cytoplasmic signaling pathways involving Rho family GTPases and nuclear hormone receptors.

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Section: Identi®cation and Cloning Of Brx Cdnasupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

et al. 1998

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“…We conclude therefore that SRC-1 is the most potent cofactor in our assay and therefore likely to be acting directly at the ERBB2 enhancer. Moreover both SRC-1 and TIF2, although widely expressed, have previously been identi®ed as competable, limiting factors particularly in the context of the squelching of progesterone receptor transactivation in the presence of ectopic ER expression (Onate et al, 1995;Voegel et al, 1996). Signi®cantly, both proteins are expressed at very modest levels in most breast tumour derived cell lines (Anzick et al, 1997;Berns et al, 1998) and levels of SRC-1 are also particularly low in patients who fail to respond to tamoxifen therapy (Berns et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer

et al. 2000

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Overexpression of the ERBB2 proto-oncogene in breast tumours, which occurs in 25 ± 30% of patients, correlates with poor prognosis. In oestrogen receptor (ER) positive breast epithelial cells oestrogens reduce ERBB2 mRNA and protein levels, an e ect that is reversed in the presence of anti-oestrogens such as tamoxifen and ICI 182780. Our previous studies have shown that the major e ect of oestrogen on ERBB2 expression is at the level of transcription and that this is mediated through a region within the ERBB2 ®rst intron which can act as an oestrogen-suppressible enhancer in ER positive breast cells. In vitro footprinting of the smallest DNA fragment that retained full activity revealed four transcription factor binding sites. We report here that two of these sites are recognized by AP-2 proteins and the other two are bound by a variety of bZIP factors, including CREB and ATF1, with a major complex containing ATFa/ JunD. However, by using ER mutants it is clear that repression occurs essentially o the DNA. Indeed, the essential domain of the ER responsible for repression of the ERBB2 enhancer is a region termed AF2 which is required for the ligand-dependent association of non-DNA binding cofactors. We further demonstrate that one of these ER cofactors, SRC-1, can relieve oestrogen repression of the ERBB2 enhancer and conclude that these data ®t with a model whereby the ER and the ERBB2 enhancer compete for this limiting, non-DNA binding cofactor. Thus, in oestrogenic conditions SRC-1 preferentially binds to the ER which e ectively sequesters it thereby reducing enhancer activity, but in antioestrogenic media the cofactor is released from the ER and is therefore available to activate the ERBB2 enhancer. Oncogene (2000) 19, 490 ± 497.

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“…ER may be able to initiate transcription by interacting with proteins that play a role in chromatin remodeling or initiation of transcription. Recently, it was demonstrated that estrogen-bound ER associates with coactivators such as SRC-1A that possess intrinsic histone acetyltransferase (HAT) activity and recruits other HATs including CBP and p/CAF to chromatin (Onate et al, 1995;Spencer et al, 1997;Smith et al, 1996;Jenster et al, 1997). In addition, CBP links steroid hormone receptors to components of the basal transcription machinery including RNA polymerase II, TATA-binding protein, TFIIB and TFIID (Kee et al, 1996;Abraham et al, 1993;Xing et al, 1995).…”

Section: Demethylation Of the Pr Cpg Island Is Not Required For Reactmentioning

confidence: 99%

“…MDA-MB-231 cells were transiently transfected with pCMV-ER, an expression vector for ER, in the presence or absence of SRC-1 (.8). SRC-1 (.8) is a dominant negative inhibitor of SRC-1A which interferes with the interaction of ER and SRC-1A, and leads to a partial inhibition of steroid hormone-responsive reporter gene activity as assayed in transiently transfected cells (Onate et al, 1995). Three independent experiments were performed in triplicate and results from one representative experiment are shown in Figure 4.…”

Section: Demethylation Of the Pr Cpg Island Is Not Required For Reactmentioning

confidence: 99%

Demethylation of the progesterone receptor CpG island is not required for progesterone receptor gene expression

1998

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Progesterone receptor (PR) is an estrogen-stimulated gene which has a CpG island that is heavily methylated in a signi®cant fraction of estrogen receptor (ER)-negative/PR-negative human breast cancers and cell lines, including MDA-MB-231 cells. Treatment of MDA-MB-231 cells with the demethylating agent, 5-aza-2'-deoxycytidine (deoxyC) led to demethylation and expression of ER and PR. However, simultaneous treatment with antiestrogen prevented PR transcription, suggesting that demethylation of PR alone is not su cient to reactivate the PR gene. To examine the e ects of ER on the methylation status of the PR CpG island, we stably transfected MDA-MB-231 cells with an inducible expression vector for ER. Surprisingly, in two cell clones, we found that induction of PR gene expression by ligand-bound ER does not require demethylation of the PR CpG island. In contrast, induction of PR transcription was inhibited by blocking the interaction of ER with SRC-1A, a coactivator of ER function. For the ®rst time, we show that a transcription factor with the potential to remodel heterochromatin can activate gene expression without altering the methylation status of the CpG island. These results raise the possibility that demethylation and histone acetylation are distinct but complementary mechanisms for destabilizing heterochromatin and activating transcription.

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Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily

Cited by 2,214 publications

References 23 publications

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer

Demethylation of the progesterone receptor CpG island is not required for progesterone receptor gene expression

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