TRAM-1, A Novel 160-kDa Thyroid Hormone Receptor Activator Molecule, Exhibits Distinct Properties from Steroid Receptor Coactivator-1

Takeshita, Akira; Cardona, Guemalli R.; Koibuchi, Noriyuki; Suen, Chen-Shian; Chin, William W.

doi:10.1074/jbc.272.44.27629

Cited by 361 publications

(214 citation statements)

References 21 publications

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“…The p160 coactivators include SRC-1 (11), GRIP1/TIF2 (12)(13)(14), and RAC3/ ACTR/AIB1/pCIP/TRAM-1 (15)(16)(17)(18)(19). These coactivators bind to the hydrophobic cleft in LBD through LXXLL motifs (20,21).…”

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confidence: 99%

Identification of a Novel Family of Ankyrin Repeats Containing Cofactors for p160 Nuclear Receptor Coactivators

Zhang

Yeung

et al. 2004

Journal of Biological Chemistry

110

112

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Members of the p160 nuclear receptor coactivators interact with liganded nuclear receptors to enhance transcription of target genes. Here we identify a novel family of ankyrin repeats containing cofactors (ANCOs) that interact with the p160 coactivators. ANCO-1 binds to the conserved Per-Arnt-Sim (PAS) region of the p160 coactivators. It encodes a large nuclear protein with five ankyrin repeats, and parts of its sequences have been reported as nasopharyngeal carcinoma susceptibility protein and medulloblastoma antigen. Immunofluorescence staining reveals discrete nuclear foci of ANCO-1 that are distinct from known nuclear structures. Intriguingly, ANCO-1 also colocalizes and interacts with histone deacetylases. Transient reporter gene assay shows that ANCO-1 expression inhibits ligand-dependent transactivation by both steroid and nonsteroid nuclear receptors. Taken together, we have identified a novel family of ankyrin repeats containing cofactors that may recruit histone deacetylases to the p160 coactivators/nuclear receptor complex to inhibit ligand-dependent transactivation.

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confidence: 99%

Identification of a Novel Family of Ankyrin Repeats Containing Cofactors for p160 Nuclear Receptor Coactivators

Zhang

Yeung

et al. 2004

Journal of Biological Chemistry

110

112

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“…A large number of nuclear receptor coactivators, often ubiquitously expressed, have been identified and characterized, and many of these coactivators utilize a conserved mechanism to recognize and interact with a ligand-bound nuclear receptor (9). Coactivators such as the p160 family SRC-1 (10), GRIP-1/ TIF2 (11,12), pCIP/ACTR/AIB1/RAC3/TRAM-1 (13)(14)(15)(16)(17), TRBP/ASC-2/RAP250 (18 -20), and TRAP220/DRIP205/PBP (21)(22)(23), interact directly with the LBD via an amphipathic ␣-helical motif with the consensus sequence LXXLL (where L is leucine and X is any amino acid), also known as a NR box (9). The conformational change induced by ligand creates a hydrophobic groove on the surface of the receptor that is bounded by two charged residues.…”

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confidence: 99%

Ligand and Coactivator Identity Determines the Requirement of the Charge Clamp for Coactivation of the Peroxisome Proliferator-activated Receptor γ

Chin

Wang

et al. 2003

Journal of Biological Chemistry

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The activation function 2 (AF-2)-dependent recruitment of coactivator is essential for gene activation by nuclear receptors. We show that the peroxisome proliferator-activated receptor ␥ (PPAR␥) (NR1C3) coactivator-1 (PGC-1) requires both the intact AF-2 domain of PPAR␥ and the LXXLL domain of PGC-1 for ligand-dependent and ligand-independent interaction and coactivation. Although the AF-2 domain of PPAR␥ is absolutely required for PGC-1-mediated coactivation, this coactivator displayed a unique lack of requirement for the charge clamp of the ligand-binding domain of the receptor that is thought to be essential for LXXLL motif recognition. The mutation of a single serine residue adjacent to the core LXXLL motif of PGC-1 led to restoration of the typical charge clamp requirement. Thus, the unique structural features of the PGC-1 LXXLL motif appear to mediate an atypical mode of interaction with PPAR␥. Unexpectedly, we discovered that various ligands display variability in terms of their requirement for the charge clamp of PPAR␥ for coactivation by PGC-1. This ligand-selective variable requirement for the charge clamp was coactivator-specific. Thus, distinct structural determinants, which may be unique for a particular ligand, are utilized by the receptor to recognize the coactivator. Our data suggest that even subtle differences in ligand structure are perceived by the receptor and translated into a unique display of the coactivator-binding surface of the ligand-binding domain, allowing for differential recognition of coactivators that may underlie distinct pharmacological profiles observed for ligands of a particular nuclear receptor.The peroxisome proliferator-activated receptor ␥ (PPAR␥), 1 is a ligand-activated nuclear receptor that plays an important role in adipogenesis and glucose homeostasis (1). Although originally identified as an orphan receptor, PPAR␥ as well as the closely related receptors, PPAR␣ (NR1C1) and PPAR␦ (NR1C2), are believed to bind to a variety of fatty acids and their metabolites (2). Synthetic agonists that activate PPAR␥, such as the thiazolidinediones, rosiglitazone, and pioglitazone, are effectively utilized in clinical practice as "insulin sensitizers" in type 2 diabetics (3). Like other nuclear receptors, PPAR␥ is comprised of several separable functional domains including a constitutively active transactivation domain, AF-1, in the amino-terminal region, a central highly conserved DNAbinding domain composed of two zinc fingers, and a ligandbinding domain (LBD) that contains a ligand-dependent transactivation function, AF-2, in its carboxyl-terminal region (4). PPAR␥ functions as an obligate heterodimer with the retinoid X receptor (RXR) and recognizes specific DNA sequences in the promoter regions of target genes referred to as peroxisome proliferator response elements (PPREs) (5). Once directed to the target gene, the transcriptional activation activity of the receptor is regulated by ligand. Ligand binding leads to a significant conformational change within the LBD that include...

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“…These coactivators interact with NRs through their LXXLL motifs (12,22,41,44), which bind to a hydrophobic cavity on the surface of the ligand-bound receptor (12,14,49). Some of the well-studied coactivators include members of the p160 family, SRC-1/NCoA-1 (30,50), SRC-2/TIF-2/ GRIP-1/NCoA-2 (23,59,61), and SRC-3/AIB1/p/CIP/ACTR/ RAC3/TRAM-1 (3,11,39,55,59); members of the CREBbinding protein (CBP)/p300 family (9,21,30), RIP140 (8), NRC/ASC-2/PRIP/RAP250/TRBP (7,31,34,41,70), PGC-1 (52), ARA70 (69), and p/CAF (5,67); and NRIF3, which exhibits specificity for only the thyroid receptors (TRs) and the retinoid X receptors (RXRs) (36,37). In addition to mediating effects of NRs, certain coactivators, including NR coregulator (NRC), appear to enhance the activity of other transcription factors such as NF-B, CREB, c-Fos, and c-Jun (31,34,40,45,46).…”

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confidence: 99%

The Nuclear Hormone Receptor Coactivator NRC Is a Pleiotropic Modulator Affecting Growth, Development, Apoptosis, Reproduction, and Wound Repair

Mahajan¹,

Das²,

Zhu³

et al. 2004

Molecular and Cellular Biology

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Nuclear hormone receptor coregulator (NRC) is a 2,063-amino-acid coregulator of nuclear hormone receptors and other transcription factors (e.g., c-Fos, c-Jun, and NF-B). We and others have generated C57BL/6-129S6 hybrid (C57/129) NRC ؉/؊ mice that appear outwardly normal and grow and reproduce. In contrast, homozygous deletion of the NRC gene is embryonic lethal. NRC ؊/؊ embryos are always smaller than NRC ؉/؉ embryos, and NRC ؊/؊ embryos die between 8.5 and 12.5 days postcoitus (dpc), suggesting that NRC has a pleotrophic effect on growth. To study this, we derived mouse embryonic fibroblasts (MEFs) from 12.5-dpc embryos, which revealed that NRC ؊/؊ MEFs exhibit a high rate of apoptosis. Furthermore, a small interfering RNA that targets mouse NRC leads to enhanced apoptosis of wild-type MEFs. The finding that C57/129 NRC ؉/؊ mice exhibit no apparent phenotype prompted us to develop 129S6 NRC ؉/؊ mice, since the phenotype(s) of certain gene deletions may be strain dependent. In contrast with C57/129 NRC ؉/؊ females, 20% of 129S6 NRC ؉/؊ females are infertile while 80% are hypofertile. The 129S6 NRC ؉/؊ males produce offspring when crossed with wild-type 129S6 females, although fertility is reduced. The 129S6 NRC ؉/؊ mice tend to be stunted in their growth compared with their wild-type littermates and exhibit increased postnatal mortality. Lastly, both C57/129 NRC ؉/؊ and 129S6 NRC ؉/؊ mice exhibit a spontaneous wound healing defect, indicating that NRC plays an important role in that process. Our findings reveal that NRC is a coregulator that controls many cellular and physiologic processes ranging from growth and development to reproduction and wound repair.

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TRAM-1, A Novel 160-kDa Thyroid Hormone Receptor Activator Molecule, Exhibits Distinct Properties from Steroid Receptor Coactivator-1

Cited by 361 publications

References 21 publications

Identification of a Novel Family of Ankyrin Repeats Containing Cofactors for p160 Nuclear Receptor Coactivators

Identification of a Novel Family of Ankyrin Repeats Containing Cofactors for p160 Nuclear Receptor Coactivators

Ligand and Coactivator Identity Determines the Requirement of the Charge Clamp for Coactivation of the Peroxisome Proliferator-activated Receptor γ

The Nuclear Hormone Receptor Coactivator NRC Is a Pleiotropic Modulator Affecting Growth, Development, Apoptosis, Reproduction, and Wound Repair

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