Yeast hormone response element assays detect and characterize GRIP1 coactivator-dependent activation of transcription by thyroid and retinoid nuclear receptors

Walfish, Paul G.; Yoganathan, Thillainathan; Yang, Yuesong; Hong, Hao; Butt, Tauseef R.; Stallcup, Michael R.

doi:10.1073/pnas.94.8.3697

Cited by 60 publications

(43 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Whether RAR homodimers may play a role in the regulation of specific target genes acting as additional modulators of physiological response to retinoic acid is not fully admitted, but some results support the possibility (11)(12)31). The formation of such homodimers is contingent upon either the nature of the coactivator interacting with RAR or the promoter context of target genes (11,13). Other NR LBDs that are known to function as heterodimers with RXR such as PPAR (21), LXRα (22) or LXRβ (23) have also been crystallized as homodimers, with the same interface as RAR, in presence of coactivator peptides.…”

Section: Discussionmentioning

confidence: 89%

“…It allowed us to unambiguously detect the origin of the conformational changes. Whether RAR homodimers may play a role in the regulation of specific target genes acting as additional modulators of physiological response to retinoic acid is not fully admitted, but some results support the possibility (11)(12)31). The formation of such homodimers is contingent upon either the nature of the coactivator interacting with RAR or the promoter context of target genes (11,13).…”

Section: Discussionmentioning

confidence: 96%

“…Their ability to form homodimers is also documented (8)(9)(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 coactivator (11). In vivo, the targeted ablation of all RXR isotypes in mouse Sertoli cells yields a phenotype distinct from that observed upon ablation of all RARs isotypes suggesting that in Sertoli cells an alternate RXR independent mechanism accounts for the RAR-mediated biological responses (12).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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.

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

See 1 more Smart Citation

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.

View full text Add to dashboard Cite

show abstract

“…Transient expression of any one of these proteins enhances transcriptional activation by hormone binding NRs and some orphan NRs (51). Antibody microinjection experiments in mammalian cells (50) and functional assays for NRs in yeast cells (24,56) indicate that these coactivators are required for efficient NR function.…”

mentioning

confidence: 99%

Multiple Signal Input and Output Domains of the 160-Kilodalton Nuclear Receptor Coactivator Proteins

Ma¹,

Hong²,

Huang³

et al. 1999

Molecular and Cellular Biology

Self Cite

229

213

View full text Add to dashboard Cite

Members of the 160-kDa nuclear receptor coactivator family (p160 coactivators) bind to the conserved AF-2 activation function found in the hormone binding domains of nuclear receptors (NR) and are potent transcriptional coactivators for NRs. Here we report that the C-terminal region of p160 coactivators glucocorticoid receptor interacting protein 1 (GRIP1), steroid receptor coactivator 1 (SRC-1a), and SRC-1e binds the N-terminal AF-1 activation function of the androgen receptor (AR), and p160 coactivators can thereby enhance transcriptional activation by AR. While they all interact efficiently with AR AF-1, these same coactivators have vastly different binding strengths with and coactivator effects on AR AF-2. p160 activation domain AD1, which binds secondary coactivators CREB binding protein (CBP) and p300, was previously implicated as the principal domain for transmitting the activating signal to the transcription machinery. We identified a new highly conserved motif in the AD1 region which is important for CBP/p300 binding. Deletion of AD1 only partially reduced p160 coactivator function, due to signaling through AD2, another activation domain located at the C-terminal end of p160 coactivators. C-terminal coactivator fragments lacking AD1 but containing AD2 and the AR AF-1 binding site served as efficient coactivators for full-length AR and AR AF-1. The two signal input domains (one that binds NR AF-2 domains and one that binds AF-1 domains of some but not all NRs) and the two signal output domains (AD1 and AD2) of p160 coactivators played different relative roles for two different NRs: AR and thyroid hormone receptor.

show abstract

“…Some of the best-characterized nuclear receptor coactivators belong to the pl60/SRC-family. This family consists of SRC-1, TIF-2/GRIP1 and AIBl/ ACTR/RAC3/TRAM-1/SRC-3 Chen et al, 1997a;Guan et al, 1996;Li et al, 1997;Onate et al, 1995;Suen et al, 1998;Takeshita et al, 1997;Voegel et al, 1996;Walfish et al, 1997). Interestingly, one of these coactivators, AIBl, was found amplified in breast, ovarian, pancreatic, and gastric cancer Ghadimi et al, 1999;Guan et al, 1996;Sakakura et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Regulation and Role of Nuclear Receptor Coactivator AIB1 in Breast Cancer

Mani¹

2004

View full text Add to dashboard Cite

Yeast hormone response element assays detect and characterize GRIP1 coactivator-dependent activation of transcription by thyroid and retinoid nuclear receptors

Cited by 60 publications

References 47 publications

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

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

Multiple Signal Input and Output Domains of the 160-Kilodalton Nuclear Receptor Coactivator Proteins

Regulation and Role of Nuclear Receptor Coactivator AIB1 in Breast Cancer

Contact Info

Product

Resources

About