Nuclear Receptor-Binding Sites of Coactivators Glucocorticoid Receptor Interacting Protein 1 (GRIP1) and Steroid Receptor Coactivator 1 (SRC-1): Multiple Motifs with Different Binding Specificities

Ding, Xiu Fen; Anderson, Carol M.; Ma, Han; Hong, Hao; Uht, Rosalie Maire; Kushner, Peter J.; Stallcup, Michael R.

doi:10.1210/mend.12.2.0065

Cited by 352 publications

(167 citation statements)

References 34 publications

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“…The activity of MN1 on the MSV-LTR, however, is stimulated significantly by the addition of ATRA, corresponding to a model in which MN1 is recruited to RAR-RXR in a hormonedependent way, for example by p160 or p300. As is obvious from experiments done by us ( Figure 5) and by others (Ding et al, 1998;Li and Chen, 1998;Voegel et al, 1998), p160 and p300 are capable of stimulating RAR-RXR in the absence of MN1. Also, the repression of MN1 activity by ElA is compatible with MN1 functioning as a coactivator that is recruited by a p300-containing complex.…”

Section: Discussionsupporting

confidence: 53%

“…A fusion bearing amino acids 365-520 only binds to p160 coactivators. These proteins interact with the ligandbinding domain of the receptors through their conserved LXXLL binding motifs (Ding et al, 1998;Li and Chen, 1998;Voegel et al, 1998). The p160 coactivators enhance transcription by way of their intrinsic HAT activity and also recruit other cofactors such as p300/ CBP (Li and Chen, 1998;Voegel et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription

et al. 2003

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The t(12;22) creates an MN1-TEL fusion gene leading to acute myeloid leukemia. The fusion partner TEL (ETV6) is a member of the ETS family of transcription factors. The nature of the other fusion partner, MN1, has not been investigated in detail until now. We recently described that MN1 activates the transcription activity of the moloney sarcoma virus long terminal repeat, indicating that this protein itself may act as a transcription factor. We show here that MN1 comprises multiple transcription activating domains. A search for a bound DNA sequence revealed that MN1 has affinity for retinoic acid responsive elements. A DR5 retinoic acid responsive element was observed in the LTR. The combination of MN1 and ligand-activated retinoic acid receptor leads to a synergistic induction of expression directed by the LTR. Cotransfection of MN1 with RAC3 or p300, known coactivators of retinoic acid receptors, leads to a further synergistic induction of transcription. In addition, the effect of MN1 can be inhibited by the wild-type adenovirus ElA protein that inhibits p300 function, but not by an E1A mutant lacking the p300-binding site. GAL4-MN1-mediated transcription can be enhanced directly by RAC3 and p300. Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription

et al. 2003

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“…Upon ligand binding, DNA-bound receptors recruit coactivators like the steroid receptor coactivator 1 (SRC-1), a member of p160 CoA family (5), to enhance target gene expression. The receptor interaction domain (RID) of the coactivators is responsible for the interaction with NRs and contains several copies of the short consensus interaction motif LXXLL (6).…”

mentioning

confidence: 99%

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Ősz

Brélivet

Peluso‐Iltis

et al. 2012

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

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Transcription regulation by steroid hormones, vitamin derivatives, and metabolites is mediated by nuclear receptors (NRs), which play an important role in ligand-dependent gene expression and human health. NRs function as homodimers or heterodimers and are involved in a combinatorial, coordinated and sequentially orchestrated exchange between coregulators (corepressors, coactivators). The architecture of DNA-bound functional dimers positions the coregulators proteins. We previously demonstrated that retinoic acid (RAR-RXR) and vitamin D3 receptors (VDR-RXR) heterodimers recruit only one coactivator molecule asymmetrically without steric hindrance for the binding of a second cofactor. We now address the problem of homodimers for which the presence of two identical targets enhances the functional importance of the mode of binding. Using structural and biophysical methods and RAR as a model, we could dissect the molecular mechanism of coactivator recruitment to homodimers. Our study reveals an allosteric mechanism whereby binding of a coactivator promotes formation of nonsymmetrical RAR homodimers with a 2∶1 stoichiometry. Ligand conformation and the cofactor binding site of the unbound receptor are affected through the dimer interface. A similar control mechanism is observed with estrogen receptor (ER) thus validating the negative cooperativity model for an established functional homodimer. Correlation with published data on other NRs confirms the general character of this regulatory pathway.allostery | structure T he superfamily of nuclear receptors (NRs) comprises liganddependent transcription factors involved in the regulation of gene expression. They constitute key drug targets for human diseases such as cancer, osteoporosis, obesity, or type II diabetes (1-2). NRs share a common structural organization with a variable amino-terminal domain, a conserved DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD) linked by a flexible hinge peptide. In addition to the ligand-binding pocket, the LBD comprises dimerization surfaces and the sites for coregulator interactions. In the classic mode of action, in absence of ligand, some NRs are associated with corepressors (NCoRs) that harbor histone-deacetylase activity to maintain the chromatin in a transcriptionally silent state (3-4). Upon ligand binding, DNA-bound receptors recruit coactivators like the steroid receptor coactivator 1 (SRC-1), a member of p160 CoA family (5), to enhance target gene expression. The receptor interaction domain (RID) of the coactivators is responsible for the interaction with NRs and contains several copies of the short consensus interaction motif LXXLL (6).The vast majority of NRs functions as dimers. RAR, like the vitamin D (VDR) and thyroid hormone (TR) receptors, heterodimerizes with rexinoid receptors (RXRs) (7). Their ability to form homodimers is also documented (8-10). RAR homodimers have been shown to be functional in yeast using a two-hybrid system, and their activity is further enhanced by the presence of SRC-2 c...

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“…GRIP1, a p160 coactivator, contains at least three NR binding motifs, NR box or LXXLL. NR box II of GRIP1 prefers to interact with ER, and NR box III strongly interacts with GR and AR (Ding et al 1998, McInerney et al 1998. Thus, the NR selectivity by NR box in GRIP1 suggests the LXXLL motif and other unidentified domains in mACTN2 may be equally important for its physical and functional interactions in various NR systems.…”

Section: Discussion the Coactivator Role Of Mactn2 In Nr Functionsmentioning

confidence: 99%

The enhancement of nuclear receptor transcriptional activation by a mouse actin-binding protein, alpha actinin 2

Huang

Huang²,

Wang³

et al. 2004

Journal of Molecular Endocrinology

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The p160 coactivators, steroid receptor coactivator 1, glucocorticoid receptor interacting protein 1 (GRIP1) and the activator of thyroid and retinoic acid receptor, have two activation domains, AD1 and AD2, which transmit the activation signal from the DNA-bound nuclear receptor to the chromatin and/or transcription machinery. In screening for mammalian proteins that bind the AD2 of GRIP1, we identified a mouse actin-binding protein, alpha actinin 2 (mACTN2). mACTN2 was expressed in the heart, skeletal muscle, lung, brain and testis, but there was no expression in the spleen, liver or kidney. Interestingly, the expression level of mACTN2 in the developing embryo depended on the embryonic stage. We further demonstrated that mACTN2 could enhance two transactivation activities of GRIP1, which in turn could enhance the homodimerization of mACTN2. Importantly, mACTN2 not only served as a primary coactivator for androgen receptor, estrogen receptor and thyroid receptor activities, but also acted synergistically with GRIP1 to enhance these nuclear receptor (NR) functions. However, the NR binding motif, LXXLL, conserved in mACTN2 and other actinin family proteins, might be a dispensable domain for its coactivator roles in NRs. These findings suggested that mACTN2 might play an important role in GRIP1-induced NR coactivator functions.

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Nuclear Receptor-Binding Sites of Coactivators Glucocorticoid Receptor Interacting Protein 1 (GRIP1) and Steroid Receptor Coactivator 1 (SRC-1): Multiple Motifs with Different Binding Specificities

Cited by 352 publications

References 34 publications

The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription

The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

The enhancement of nuclear receptor transcriptional activation by a mouse actin-binding protein, alpha actinin 2

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