Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor

Hörlein, Andreas; Näär, Anders M.; Heinzel, Thorsten; Torchia, Joseph; Gloss, Bernd; Kurokawa, Riki; Ryan, Aimee K.; Kamei, Yasutomi; Söderström, Mats; Glass, Christopher K.; Rosenfeld, Michael G.

doi:10.1038/377397a0

Cited by 1,889 publications

(1,482 citation statements)

References 48 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: 55%

“…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: 55%

Section: Introductionmentioning

confidence: 99%

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

et al. 1998

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“…A triple-point mutation (AHT-GGA) in the CoR box located in H1 blocks interaction with SMRT and NCoR (Ho¨rlein et al, 1995;Perissi et al, 1999;Marimuthu et al, 2002) and appears to affect the overall structure of the LBD (Pissios et al, 2000). In addition, the P214R mutant in a residue preceding H1 was reported to lack silencing activity without altering LBD stability (Tagami et al, 1997;Pissios et al, 2000).…”

Section: Trb1 Domains Involved In Transrepression Of the Cyclin D1 Prmentioning

confidence: 99%

Thyroid hormone receptor β1 domains responsible for the antagonism with the ras oncogene: role of corepressors

et al. 2010

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The thyroid hormone receptor (TR) is a suppressor of rasmediated responses. To characterize the receptor domains involved in this function, we analyzed a panel of TRb1 mutants for their ability to interfere with ras-driven cyclin D1 activation, formation of transformation foci and tumor growth in nude mice. Our results show that the domains and mechanisms responsible for the anti-transforming and anti-tumorigenic actions of the receptor are divergent from those operating in classical T3-dependent transcriptional activation. TRb1 mutants that do not bind coactivators and do not transactivate retained the capacity of suppressing cellular transformation and tumor growth, whereas selective mutations in the hinge region affecting corepressors recruitment abolished these actions, while preserving ligand-dependent transcription. There was a strict parallelism between anti-transforming activity of the various mutants and their ability to antagonize cyclin D1 stimulation by ras, indicating that transrepression mechanisms may have an important function in suppression of the transforming effects of the oncogene by TRb1. The inhibitory action of T3 on transformation was further enhanced after over-expression of corepressors, while corepressor depletion by means of small-interference RNA reversed significantly hormonal action. This shows an important functional role of endogenous corepressors in suppression of ras-mediated transformation and tumorigenesis by TRb1

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“…Alternatively, it was shown that v-erb A interacts with recently discovered co-repressors N-Cor or SMRT (Horlein et al, 1995;Chen and Evans, 1995). It could compete with c-erb A in equimolar ratio for N-Cor or SMRT interaction, thus derepressing basal transcription rate.…”

Section: V-erb a Induces A T3 Independent C-erb A Activity In Avian Mmentioning

confidence: 99%

Molecular basis of the cell-specific activity of v-erb A in quail myoblasts

et al. 1997

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We have previously shown that v-erb A expression strongly stimulates quail myoblast proliferation and di erentiation without alteration of the triiodothyronine (T3) in¯uence in this cell type. In order to understand the molecular basis of v-erb A action in myoblasts, we have studied the in¯uence of this oncoprotein on c-erb Aa1 encoded T3 nuclear receptor (TRa) activity. In transfection experiments, v-erb A did not inhibit the T3-dependent c-erb Aa1 transcriptional activity in QM7 myoblasts in contrast to its action in HeLa cells. However, it repressed the retinoic acid receptor RARa activity in both cell-types, indicating that v-erb A interactions with T3 or RA mediated transcription signi®cantly di ers. In EMSA experiments using a TRE pa1 probe, T3Ra binds as three complexes in HeLa cells. We have previously identi®ed the slow migrating complex, undetectable in QM7 myoblasts, as a T3R/ RXR heterodimer. Interestingly, v-erb A inhibited binding of this complex in HeLa cells, but did not a ect binding of the two other complexes in QM7 myoblasts. Expression of RXR (g isoform), the TRa dimerization partner absent in proliferating QM7 cells, restored inhibition of c-erb Aa1 transcriptional activity in these cells and abrogated the v-erb A myogenic in¯uence. Lastly, v-erb A induced a T3-independent cerb Aa1 activity in QM7 cells when cotransfected in equimolar ratio with the receptor, by inhibiting AP-1 activity and stimulating transcription of a reporter gene driven by a TRE sequence.

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Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor

Cited by 1,889 publications

References 48 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

Thyroid hormone receptor β1 domains responsible for the antagonism with the ras oncogene: role of corepressors

Molecular basis of the cell-specific activity of v-erb A in quail myoblasts

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