Molecular determinants of nuclear receptor-corepressor interaction

Perissi, Valentina; Staszewski, Lena M.; McInerney, Eileen M.; Kurokawa, Riki; Krones, Anna; Rose, David W.; Lambert, Mill H.; Milburn, Michael V.; Glass, Christopher K.; Rosenfeld, Michael G.

doi:10.1101/gad.13.24.3198

Cited by 472 publications

(383 citation statements)

References 60 publications

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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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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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“…Two sequences in the C-terminal regions of N-CoR and SMRT appear to function cooperatively to mediate interactions with DNAbound thyroid hormone receptor/RXR heterodimers, each containing a conserved consensus sequence LXXXIXXX(I/L) that mediate interactions with unliganded thyroid and retinoic acid receptors (63)(64)(65). This motif is predicted to form an extended ␣ helix, one helical turn longer than the LXXLL recognition motif present in nuclear receptor coactivators.…”

Section: Determination Of N-cor/smrt Receptor Interactorsmentioning

confidence: 99%

Coregulator Codes of Transcriptional Regulation by Nuclear Receptors

Rosenfeld¹,

Glass²

2001

Journal of Biological Chemistry

467

371

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Members of the nuclear receptor superfamily directly activate or repress target genes by binding to hormone response elements (HREs) 1 in promoter or enhancer regions, and by binding to other DNA sequence-specific activators and can inhibit the transcriptional activities of other classes of transcription factors by transrepression. Hormone response elements provide specificity to receptor homodimer heterodimer binding (reviewed in Ref.2). Nuclear receptor functions are directed by specific activation domains, referred to as activation function 1 (AF-1), which resides in the N terminus, and activation function 2 (AF-2), which resides in the C-terminal ligand binding domain (LBD) (reviewed in Ref. 1). Regulation of gene transcription by nuclear receptors requires the recruitment of proteins characterized as coregulators, with liganddependent exchange of corepressors for coactivators serving as the basic mechanism for switching gene repression to activation. In this review, we discuss biochemical and genetic studies suggesting that coregulatory complexes are differentially utilized in both a cell-and promoter-specific fashion to activate or repress gene transcription. These coregulatory components, themselves targets of diverse intracellular signaling pathways, provide a combinatorial code for tissue-and gene-specific responses, utilizing both enzymatic and platform assembly functions to mediate the actions of nuclear receptor genetic programs critical for developmental and homeostatic processes in metazoan organisms. Nuclear Receptor CoactivatorsA diverse group of proteins have emerged as potential coactivators for nuclear receptors. Ligand-dependent recruitment of coactivators is dependent on AF-2, which consists of a short conserved helical sequence within the C terminus of the LBD (2). Biochemical and expression cloning approaches have been used to identify a large number of factors that interact with nuclear receptors in either a ligand-independent or a ligand-dependent manner and are often components of large multiprotein complexes. Many of these factors are capable of potentiating nuclear receptor activity in transient cotransfection assays. In addition, a distinct set of coactivators is associated with the AF-1 domain. As the number of potential coregulators clearly exceeds the capacity for direct interaction by a single receptor, the most plausible hypothesis is that transcriptional activation by nuclear receptors involves the actions of multiple factors. These factors act in a sequential and/or combinatorial manner to reorganize chromatin templates and to modify and recruit basal factors and RNA polymerase II (3, 4). ATP-dependent Chromatin Remodeling ComplexesAs chromatinized transcription units are "repressed" compared with naked DNA, a critical aspect of gene activation involves nucleosomal remodeling (reviewed in Refs. 3-5). Two general classes of chromatin remodeling factors that appear to play critical roles in transcriptional activation by nuclear receptors have been identified. These are ATP-depen...

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“…Co-repressors (N-CoR/SMRT) can be recruited to interacting surfaces located on the LBD surface of nuclear receptors, which partially overlaps with that used by P160 co-activators [34][35][36]. Repression of DHTactivated AR by N-CoR only requires the repressor interaction domains, and is independent of N-CoR domains that can recruit histone deacetylases [27].…”

Section: Competition Between Tif2 and N-cor Is Ligand-type-dependentmentioning

confidence: 99%

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

Berrevoets

Umar

Trapman

et al. 2004

Biochemical Journal

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Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)-and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonistbound AR has a preference for N-CoR. The AR mutation T877A (Thr 877 → Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of NCoR. The agonistic activities of CPA-and hydroxyflutamideoccupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.

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Molecular determinants of nuclear receptor-corepressor interaction

Cited by 472 publications

References 60 publications

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

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

Coregulator Codes of Transcriptional Regulation by Nuclear Receptors

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

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