The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion

Abstract

Cognate cDNAs are described for 2 of the 10 thyroid hormone receptor-associated proteins (TRAPs) that are immunopurified with thyroid hormone receptor α (TRα) from ligand-treated HeLa (α-2) cells. Both TRAP220 and TRAP100 contain LXXLL domains found in other nuclear receptor-interacting proteins and both appear to reside in a single complex with other TRAPs (in the absence of TR). However, only TRAP220 shows a direct ligand-dependent interaction with TRα, and these interactions are mediated through the C terminus of TRα and (at least in part) the LXXLL domains of TRAP220. TRAP220 also interacts with other nuclear receptors [vitamin D receptor, retinoic acid receptor α, retinoid X receptor α, peroxisome proliferation-activated receptor (PPAR) α, PPARγ and, to a lesser extent, estrogen receptor] in a ligand-dependent manner, whereas TRAP100 shows only marginal interactions with estrogen receptor, retinoid X receptor α, PPARα, and PPARγ. Consistent with these results, TRAP220 moderately stimulates human TRα-mediated transcription in transfected cells, whereas a fragment containing the LXXLL motifs acts as a dominant negative inhibitor of nuclear receptor-mediated transcription both in transfected cells (TRα) and in cell free transcription systems (TRα and vitamin D receptor). These studies indicate that TRAP220 plays a major role in anchoring other TRAPs to TRα during the function of the TRα–TRAP complex and, further, that TRAP220 (possibly along with other TRAPs) may be a global coactivator for the nuclear receptor superfamily.

Functional significance of the two ACOX1 isoforms and their crosstalks with PPARα and RXRα

“…4 At the transcriptional level, PPARa, which forms a heterodimer with retinoid X receptor (RXR), 5,6 binds to peroxisome proliferator-responsive element (PPRE) present in the 5 0 -flanking region of target genes. [6][7][8] In the presence of a ligand, PPAR-RXR complexes recruit coactivators, such as steroid receptor coactivator-1 (SRC-1) and PPAR-binding protein/Mediator 1 (PBP/TRAP220/Med1) 9,10 to enhance target gene transcription. [9][10][11] The generation of PparaÀ/À mice established that PPARa is essential for hepatic peroxisome proliferation and coordinates transcriptional activation of genes coding for ACOX1, L-peroxisomal bifunctional enzyme (L-PBE), peroxisomal thiolase (PTL), cytochrome P 450 4A10 (CYP4A10) and cytochrome P 450 4A14 (CYP4A14), and other lipid metabolism-related key enzymes by structurally diverse synthetic peroxisome proliferators, as well as by several fatty acids and their polyunsaturated derivatives.…”

“…[6][7][8] In the presence of a ligand, PPAR-RXR complexes recruit coactivators, such as steroid receptor coactivator-1 (SRC-1) and PPAR-binding protein/Mediator 1 (PBP/TRAP220/Med1) 9,10 to enhance target gene transcription. [9][10][11] The generation of PparaÀ/À mice established that PPARa is essential for hepatic peroxisome proliferation and coordinates transcriptional activation of genes coding for ACOX1, L-peroxisomal bifunctional enzyme (L-PBE), peroxisomal thiolase (PTL), cytochrome P 450 4A10 (CYP4A10) and cytochrome P 450 4A14 (CYP4A14), and other lipid metabolism-related key enzymes by structurally diverse synthetic peroxisome proliferators, as well as by several fatty acids and their polyunsaturated derivatives. [12][13][14][15] Although fatty acids are metabolized by the mitochondrial and peroxisomal b-oxidation enzyme systems with partly overlapping substrate specificities, 3,16 the oxidation of the major fraction of medium and long-chain fatty acids (LCFAs, C12-C18) occurs in the mitochondria, whereas oxidation of VLCFAs takes place almost exclusively in peroxisomes.…”

Drosophila homologs of transcriptional mediator complex subunits are required for adult cell and segment identity specification

“…A previous study of the C. elegans sur-2 gene focused on its role as a genetic suppressor of a Ras/MAP kinase pathway in vulval development, indicating a functional connection between cell signaling and mediator function (Singh and Han 1995). The human TRAP and DRIP complexes were identified by their biochemical interactions with thyroid and vitamin D 3 nuclear hormone receptors, and a different subunit, human TRAP220, mediates ligand-specific complex binding to several nuclear receptors (Yuan et al 1998). The heightened affinity of this specific ligandbound complex and its enhancement of in vitro transcription, in contrast to the nuclear receptor-TRAP220 couple, seems likely to represent a recurrent theme for MED utilization in the dynamic expression of genetic programs during development.…”

The Mediator Complex in Plants: Structure, Phylogeny, and Expression Profiling of Representative Genes in a Dicot (Arabidopsis) and a Monocot (Rice) during Reproduction and Abiotic Stress

“…Despite a rigorous search, only the red alga C. merolae had a detectable Med1 subunit in the plant kingdom. Med1 is the target for the aryl-hydrocarbon receptor (Wang et al, 2004) and several liganded nuclear receptors via its LxxLL (Leu-X-X-Leu-Leu) motif (Yuan et al, 1998;Malik et al, 2002). CmMed1_1 has two LxxLL motifs at positions 219 and 384.…”