Nuclear receptor coactivators and corepressors.

Horwitz, Kathryn B.; Jackson, Twila A.; Bain, David L.; Richer, Jennifer K.; Takimoto, Glenn S.; Tung, Lin

doi:10.1210/mend.10.10.9121485

Cited by 458 publications

(420 citation statements)

References 49 publications

Supporting

Mentioning

412

Contrasting

Unclassified

Order By: Relevance

“…They influence the magnitude of transcriptional activation or repression and alter the dose-responsive profiles to the ligands depending on the natures of the ligand (6). The involvement of coregulators, coactivators such as SRC-1, GRIP-1, and corepressors, such as SMRT (silencing mediator for retinoid and thyroid hormone receptor), nuclear receptor corepressor-1, in transcriptional regulation by the ER is now well established (32,33). Therefore, we tested the possibility that CAR interferes with the ER transactivation by squelching the ER coactivators, GRIP-1 and SRC-1.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Cross-talk between Estrogen Receptor (ER) and Constitutively Activated Androstane Receptor (CAR)

Min

Kim

Bae

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Estrogen receptor (ER) activity can be modulated by the action of other nuclear receptors. To study whether ER activity is altered by orphan nuclear receptors that mediate the cellular response to xenobiotics, cross-talk between ER and constitutive androstane receptor (CAR), steroid and xenobiotic receptor, or peroxisome proliferator-activated receptor ␥ was examined in HepG2 cells. Of these receptors, CAR substantially inhibited ER-mediated transcriptional activity of the vitellogenin B1 promoter as well as a synthetic estrogen responsive element (ERE)-containing promoter. Treatment with an agonist of CAR, 1,4-bis-(2-(3,5-dichloropyridoxyl))benzene, potentiated CAR-mediated transcriptional repression. In contrast, an antagonist of CAR, androstenol, alleviated the repression effect. Although CAR interacted with the ER in solution, CAR did not interact with the ER bound to the ERE. CAR/retinoid X receptor bound to the ERE but with much lower affinity than ER. Incremental amounts of CAR elicited a progressive reduction of the ER activity induced by the p160 coactivator glucocorticoid receptor interacting protein 1 (GRIP-1). In turn, increasing amounts of GRIP-1 progressively reversed the depression of ER activity by CAR. An agonist or antagonist of CAR potentiated or alleviated, respectively, the CAR-mediated repression of the GRIP-1-enhanced ER activity, which is consistent with the ability of theses ligands to increase or decrease, respectively, the interaction of CAR with GRIP-1. A CAR mutant that did not interact with GRIP-1 did not inhibit ER-mediated transactivation. Our data demonstrate that xenobiotic nuclear receptor CAR antagonizes ER-mediated transcriptional activity by squelching limiting amounts of p160 coactivator and imply that xenobiotics may influence ER function of female reproductive physiology, cell differentiation, tumorigenesis, and lipid metabolism.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibitory Cross-talk between Estrogen Receptor (ER) and Constitutively Activated Androstane Receptor (CAR)

Min

Kim

Bae

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Corepressors physically bind to T3Rs and RARs in the absence of hormone, a context in which these receptors typically repress. Addition of hormone leads to release of the corepressor, the association of coactivators, and conversion of the receptor to a positive enhancer of transcription (26)(27)(28)(29)(30)(31)(32)(33)(34). Given the central role of corepressors in the actions of the normal RARs, we examined the role of these cofactors in the actions of the PML-RAR␣ and PLZF-RAR␣ oncoproteins.…”

Section: Discussionmentioning

confidence: 99%

“…Addition of hormone converts these receptors into transcriptional activators, a process that correlates with dissociation of the corepressors from the receptor and a corresponding recruitment of a novel set of coactivator proteins (26)(27)(28)(29)(30)(31)(32)(33)(34). In vertebrates, corepressors are encoded by two known, interrelated loci, denoted SMRT (or TRAC) and N-CoR (or RIP13), with each locus expressed as a variety of alternatively spliced mRNAs (e.g., TRAC-1, TRAC-2, RIP13A; refs.…”

mentioning

confidence: 99%

SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor α (RARα) and PLZF-RARα oncoproteins associated with acute promyelocytic leukemia

Hong

Gourichon

Wong

et al. 1997

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

327

277

View full text Add to dashboard Cite

Retinoic acid receptors (RARs) are hormone-regulated transcription factors that control key aspects of normal differentiation. Aberrant RAR activity may be a causal factor in neoplasia. Human acute promyelocytic leukemia, for example, is tightly linked to chromosomal translocations that fuse novel amino acid sequences (denoted PML, PLZF, and NPM) to the DNA-binding and hormone-binding domains of RAR␣. The resulting chimeric receptors have unique transcriptional properties that may contribute to leukemogenesis. Normal RARs repress gene transcription by associating with ancillary factors denoted corepressors (also referred to as SMRT, N-CoR, TRAC, or RIP13). We report here that the PML-RAR␣ and PLZF-RAR␣ oncoproteins retain the ability of RAR␣ to associate with corepressors, and that this corepressor association correlates with certain aspects of the leukemic phenotype. Unexpectedly, the PLZF moiety itself can interact with SMRT corepressor. This interaction with corepressor is mediated, in part, by a POZ motif within PLZF. Given the presence of POZ motifs in a number of known transcriptional repressors, similar interactions with SMRT may play a role in transcriptional silencing by a variety of both receptor and nonreceptor transcription factors.Retinoids regulate many aspects of vertebrate cell proliferation and differentiation through receptors that function as hormone-regulated transcription factors (1-6). Two major classes of retinoid receptors have been identified: retinoic acid receptors (RARs) and retinoid X receptors (RXRs) (3-6). Both RARs and RXRs bind to specific sites on the DNA, and they can activate or repress expression of adjacent target genes (1-6). Aberrant RARs appear to play a crucial role in human acute promyelocytic leukemia (APL) (7-15). In over 95% of all APL patients, specific chromosomal translocations create abnormal RARs by replacing the N terminus of RAR␣ with novel ORFs. The breakpoint in RAR␣ is identical in all cases, whereas the nature of the novel N-terminal sequences can vary. In the common t(15;17) translocation, the RAR␣ N terminus is replaced with an ORF denoted PML (for promyelocytic leukemia) (7-12). Alternatively, t(11;17) and t(5;17) translocations result in chimeric proteins denoted PLZF (promyelocytic leukemia zinc finger)-RAR␣ and NPM (nucleophosmin)-RAR␣, respectively (13-15). Although possessing a number of recognizable structural motifs, including several prevalent in transcription factors, the PML, PLZF, and NPMderived sequences exhibit little structural interrelatedness, and the functions of these proteins in the normal cell are not fully understood (reviewed in refs. 16-18).The near-invariant association of acute promyelocytic leukemia with the expression of chimeric RAR␣ proteins, and the ability of retinoids to drive leukemias bearing the PML-RAR␣ translocation into differentiation and clinical remission (16-18), suggest an active role for these chimeras in conferring the leukemogenic phenotype. Furthermore, ectopic expression of PML-RAR␣ in murine or av...

show abstract

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1998

View full text Add to dashboard Cite

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.

show abstract

Nuclear receptor coactivators and corepressors.

Cited by 458 publications

References 49 publications

Inhibitory Cross-talk between Estrogen Receptor (ER) and Constitutively Activated Androstane Receptor (CAR)

Inhibitory Cross-talk between Estrogen Receptor (ER) and Constitutively Activated Androstane Receptor (CAR)

SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor α (RARα) and PLZF-RARα oncoproteins associated with acute promyelocytic leukemia

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

Contact Info

Product

Resources

About