Many transcription coactivators interact with nuclear receptors in a ligandThe nuclear receptor superfamily is a group of proteins that regulate, in a ligand-dependent manner, transcriptional initiation of target genes by binding to specific DNA sequences named hormone response elements (reviewed in reference 23). Functional analysis of nuclear receptors has shown that there are two major activation domains. The N-terminal domain (AF1) contains a ligand-independent activation function, whereas the ligand-binding domain (LBD) exhibits ligand-dependent transactivation function (AF2). The AF2 core region, located at the extreme C terminus of the receptor LBDs, is conserved among nuclear receptors and undergoes a major conformational change upon ligand binding (23). This region has been shown to play a critical role in mediating transactivation by serving as a ligand-dependent interaction interface with many different coactivators (reviewed in reference 9). These coactivators, including the p160 family members (i.e., SRC-1, SRC-2/GRIP1/TIF2, and SRC-3/ACTR/pCIP/AIB1/ RAC3/TRAM1), CBP/p300, p/CAF, TRAP/DRIP, activating signal cointegrator 2 (ASC-2), and many others, bridge nuclear receptors and the basal transcription apparatus and/or remodel the chromatin structures (9).Chromatin, the physiological template of all eukaryotic genetic information, undergoes a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA (reviewed in reference 12). SRC-1 and the p160 family member ACTR, along with CBP and p300, were recently shown to contain histone acetyltransferase (HAT) activities and associate with yet another HAT protein, p/CAF (9). In contrast, SMRT and N-CoR, nuclear receptor corepressors, form complexes with Sin3 and histone deacetylase proteins (9). These results are consistent with the notion that the acetylation of histones destabilizes nucleosomes and relieves transcriptional repression by allowing transcription factors to access recognition elements, whereas deacetylation of the histones stabilizes the repressed state. More recently, the histone arginine methyltransferases CARM1 and PRMT1 were newly defined as transcriptional coactivators of nuclear receptors (4, 40). NSD1 and

Transcriptional coactivators either bridge transcription factors and the components of the basal transcription apparatus and/or remodel the chromatin structures. We isolated a novel nuclear protein based on its interaction with the recently described general coactivator activating signal cointegrator-2 (ASC-2). This protein CAPER (for coactivator of activating protein-1 (AP-1) and estrogen receptors (ERs)) selectively bound, among the many transcription factors we tested, the AP-1 component c-Jun and the estradiol-bound ligand binding domains of ER␣ and ER␤. Interestingly, CAPER exhibited a cryptic autonomous transactivation function that becomes activated only in the presence of estradiol-bound ER. In cotransfections, CAPER stimulated transactivation by ER␣, ER␤, and AP-1. Thus, CAPER may represent a more selective transcriptional coactivator molecule that plays a pivotal role for the function of AP-1 and ERs in vivo in conjunction with the general coactivator ASC-2.The activation protein-1 (AP-1) 1 transcription factors are immediate early response genes involved in a diverse set of transcriptional regulatory processes (for a review see Ref. 1). The AP-1 complex consists of a heterodimer of a Fos family member and a Jun family member. This complex binds the consensus DNA sequence (TGAGTCA) (termed AP-1 sites) found in a variety of promoters. The Fos family contains four proteins (c-Fos, Fos-B, Fra-1, and Fra-2), whereas the Jun family is composed of three proteins (c-Jun, Jun-B, and Jun-D). Fos and Jun are members of the basic region-leucine zipper (bZIP) family of sequence-specific dimeric DNA-binding proteins (1). The C-terminal half of the bZIP domain is amphipathic, containing a heptad repeat of leucines that is critical for the dimerization of bZIP proteins, whereas the N-terminal half of the long bipartite helix is the basic region that is responsible for the sequence-specific DNA binding.The nuclear receptor superfamily is a group of ligand-dependent transcriptional regulatory proteins that function by binding to specific DNA sequences named hormone-response elements in the promoters of target genes (reviewed in Ref.2). The superfamily includes receptors for a variety of small hydrophobic ligands such as steroids, triiodothyronine, and retinoids as well as a large number of related proteins that do not have known ligands, referred to as orphan nuclear receptors. The C terminus of the ligand binding domain of these proteins harbors an essential ligand-dependent transactivation function, activation function 2 (AF2), whereas the N terminus of many nuclear receptors often includes AF1.Genetic studies implicated that transcription coregulators (or cofactors) with no specific DNA binding activity are essential components of transcriptional regulation, which ultimately led us to identify a series of coregulatory proteins (for reviews, see Refs. 3 and 4). They appear to function by either remodeling chromatin structures and/or acting as adapter molecules between transcription factors and the components of the b...

Human activating signal cointegrator 1 (hASC-1) was originally isolated as a transcriptional coactivator of nuclear receptors. Here we report that ASC-1 exists as a steady-state complex associated with three polypeptides, P200, P100, and P50, in HeLa nuclei; stimulates transactivation by serum response factor (SRF), activating protein 1 (AP-1), and nuclear factor B (NF-B) through direct binding to SRF, c-Jun, p50, and p65; and relieves the previously described transrepression between nuclear receptors and either AP-1 or NF-B. Interestingly, ectopic expression of Caenorhabditis elegans ASC-1 (ceASC-1), an ASC-1 homologue that binds P200 and P100, like hASC-1, while weakly interacting only with p65, in HeLa cells appears to replace endogenous hASC-1 from the hASC-1 complex and exerts potent dominant-negative effects on AP-1, NF-B, and SRF transactivation. In addition, neutralization of endogenous P50 by single-cell microinjection of a P50 antibody inhibits AP-1 transactivation; the inhibition is relieved by coexpression of wild-type P50, but not of P50⌬KH, a mutant form that does not interact with P200. Overall, these results suggest that the endogenous hASC-1 complex appears to play an essential role in AP-1, SRF, and NF-B transactivation and to mediate the transrepression between nuclear receptors and either AP-1 or NF-B in vivo.

Nuclear receptors, many of which undergo a major conformational change upon binding specific ligand, belong to a superfamily of proteins that bind to specific DNA sequences and control gene transcription. They regulate the assembly of a transcriptional preinitiation complex at the promoter of target genes and modulate their expression in response to ligand. In particular, nuclear receptors repress or stimulate transcription by recruiting corepressor or coactivator proteins, in addition to directly contacting the basal transcription machinery. In this review, we discuss recent progress in studies of these transcriptional coregulators of nuclear receptors.

Small heterodimer partner (SHP), specifically expressed in liver and a limited number of other tissues, is an unusual orphan nuclear receptor that lacks the conventional DNA binding domain. In this work, we found that SHP expression is abundant in murine macrophage cell line RAW 264.7 but was suppressed by oxidized low density lipoprotein (oxLDL) and its constituent 13-hydroxyoctadecadienoic acid, a ligand for peroxisome proliferator-activated receptor ␥. Furthermore, SHP acted as a transcription coactivator of nuclear factor-B (NFB) and was essential for the previously described NFB transactivation by palmitoyl lysophosphatidylcholine, one of the oxLDL constituents. Accordingly NFB, which was transcriptionally active in the beginning, became progressively inert in oxLDL-treated RAW 264.7 cells as oxLDL decreased the SHP expression. Thus, SHP appears to be an important modulatory component to regulate the transcriptional activities of NFB in oxLDL-treated, resting macrophage cells.The nuclear receptor superfamily includes receptors for a variety of small hydrophobic ligands such as steroids, T3, and retinoids as well as a large number of related proteins that do not have known ligands, referred to as orphan nuclear receptors (for review, see Ref. 1). The receptor proteins are direct regulators of transcription that function by binding to specific DNA sequences named hormone response elements in promoters of target genes. Nearly all the superfamily members bind as dimers to DNA elements. Although some apparently bind only as homodimers, thyroid hormone receptors, vitamin D receptor, retinoic acid receptors (RARs), 1 the peroxisome proliferatoractivated receptors (PPARs), and several orphan nuclear receptors bind their specific response elements with high affinity as heterodimers with the retinoid X receptors. Receptors have dimerization interfaces in both their DNA binding domain and ligand binding domain. The DNA binding domain interfaces are quite different for each receptor, whereas the ligand binding domain interface is primarily based on a conserved motif referred to as the ninth heptad or the I-box (2). This motif is required for both heterodimerization and homodimerization of many nuclear receptors, including retinoid X receptor, thyroid hormone receptor, RAR, hepatocyte nuclear factor 4, and chicken ovalbumin upstream promoter transcription factor (2-4). Small heterodimer partner (SHP) is an orphan nuclear receptor specifically expressed in liver and a limited number of other tissues, and its activities are in some ways opposite to those of retinoid X receptor (5). SHP, like the orphan nuclear receptor DAX-1 (for review, see Ref. 6), lacks the conventional DNA binding domain. Both direct biochemical and the yeast two-hybrid results demonstrated that SHP interacts with many members of the receptor superfamily (5). As expected from its lack of a DNA binding domain, addition of SHP inhibited in vitro DNA binding by nuclear receptors with which it interacted, and in mammalian cell cotransfections, SHP repress...