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PubMed1996

Nuclear receptor coactivators and corepressors.

The nuclear receptors belong to a superfamily of proteins, many of which are ligand-regulated, that bind to specific DNA sequences and control specific gene transcription. Recent data show that, in addition to contacting the basal transcription machinery directly, nuclear receptors inhibit or enhance transcription by recruiting an array of coactivator or corepressor proteins to the transcription complex. In this review we define the properties of these putative coregulatory factors; we describe the basal and coregulatory factors that are currently known to interact with nuclear receptors; we suggest various mechanisms by which coactivators and corepressors act; we discuss issues that are raised by the presence of multiple, perhaps competing, coregulatory factors; and we speculate how these additional regulatory layers may explain the heterogeneity of hormone responses that are observed in normal and malignant tissues.

Animals↗
PubMed2005

Modulation of hormonal signaling in the brain by steroid receptor coactivators.

Nuclear receptors, such as estrogen, glucocorticoid or thyroid hormone receptors, have been shown to play a critical role in brain development and physiology. The activity of these receptors is modulated by the interaction with several proteins and, in particular, coactivators are required to enhance their transcriptional activity. The steroid receptor coactivators (SRC-1, -2 and -3) are currently the best characterized coactivators and we review here the current knowledge on the distribution and function of these proteins in the brain. Knock-out models and antisense techniques have demonstrated the requirement for SRC-1 and -2 in the brain, focusing mainly on steroid and thyroid hormone-dependent development and behavior. The precise function of SRC-3 in the brain is currently unknown but its presence throughout the brain suggests an important function. Although the molecular biology of SRCs is relatively well known, the in vivo control of their expression, post-translational modifications and time- and cell-specific interactions with the different nuclear receptors remain elusive. A complete understanding of hormone action on brain and behavior will not be attained until a better knowledge of coactivator physiology is achieved.

Animals↗
PubMed2002

Molecular structure and biological function of the cancer-amplified nuclear receptor coactivator SRC-3/AIB1.

Nuclear hormone receptors are ligand-dependent transcription factors that require coactivators to regulate target gene expression. The steroid receptor coactivator-3 (SRC-3), also known as p/CIP, RAC3, AIB1, ACTR and TRAM-1, is a cancer-amplified coactivator in the SRC gene family that also contains SRC-1 and TIF2/GRIP1. SRC-3 interacts with nuclear receptors and certain other transcription factors, recruits histone acetyltransferases and methyltransferases for chromatin remodeling and facilitates target gene transcription. Accumulated results from both ex vivo and animal model studies indicate that SRC-3 plays important roles in many biological processes involving cell proliferation, cell migration, cell differentiation, somatic growth, sexual maturation, female reproductive function, vasoprotection and breast cancer. This article summarizes our current knowledge about SRC-3 under the following topics: molecular cloning and characterization; molecular structure and functional mechanisms; SRC-3 as a molecular target of growth factors and cytokines; organization and expression of the SRC-3 gene; generation and characterization of SRC-3 knockout mice; role of SRC-3 in the vasoprotective effects of estrogen; role of SRC-3 in cell migration, proliferation and cancers.

Acetyltransferases↗
PubMedDate not supplied

Vitamin D receptor and nuclear receptor coactivators: crucial interactions in vitamin D-mediated transcription.

The nuclear actions of 1,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] are mediated by the vitamin D receptor (VDR). Binding of ligand induces conformational changes in the VDR which promote heterodimerization with retinoid X receptor (RXR) and recruitment of a number of nuclear receptor coactivator proteins including the steroid receptor coactivator (SRC) family members, select SMAD proteins, a novel coactivator complex referred to as DRIP, and a variety of other putative factors. We recently described a novel nuclear receptor coactivator termed NCoA-62 that interacts with the VDR to enhance 1alpha,25(OH)(2)D(3)-activated transcription. NCoA-62 is unrelated to the SRC family, the DRIP complex, as well as other nuclear receptor coactivators described thus far. The molecular mechanisms involved in NCoA-62 coactivator function are poorly understood, but protein-protein interactions are likely to play an important role. The purpose of this paper is to briefly review salient features of the coactivators involved in VDR-activated transcription and to focus on our current understanding of NCoA-62 and its interplay with other nuclear receptor coactivator proteins. It is clear from the studies described here that a concerted series of interactions with multiple coactivator proteins are essential for high order transactivation by 1alpha,25(OH)(2)D(3) and the VDR.

Animals↗
PubMed1997

Nuclear receptor coactivators.

Retinoic acid, steroid and thyroid hormones regulate complex programs of gene expression by binding to intracellular receptors that are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Recent studies have led to the identification and cloning of genes encoding coactivator molecules that appear to play important roles in mediating ligand-dependent transcription by members of this family. The identification of these coactivator molecules suggests a point of entry into the general transcriptional machinery that is common to several other classes of regulated transcription factors.

Allosteric Regulation↗
PubMed2000

Nuclear receptor coactivators facilitate vitamin D receptor homodimer action on direct repeat hormone response elements.

Vitamin D receptor (VDR) is a ligand-dependent transcription factor that regulates target gene expression. Although VDR forms stable heterodimer complex with retinoid X receptors (RXRs) on vitamin D-response elements (VDREs), it is still not clear whether VDR/RXR heterodimers are the only VDR complexes responsible for vitamin D-mediated gene transcription. In this report, we analyzed the effect of nuclear receptor coactivators (SRC-1 and TRAM-1) on VDR homodimer and VDR/RXR heterodimer formation by electrophoretic mobility shift assay. We found that VDR forms stable homodimers after interaction with the coactivators on a VDRE (DR+3). Of particular note, DR+4 and DR+5 hormone-response elements (HREs) may also support such interactions. Cotransfection experiments revealed further that the coactivators enhance ligand-induced VDR transcription on these elements. Our studies suggest the important role of VDR homodimers, in addition to VDR/RXR heterodimers, in vitamin D-induced transactivation. Thus, specific coactivator-VDR interactions on HREs may determine target gene transactivation.

Cell Nucleus↗
PubMed2002

Nuclear receptor coactivators modulate hormone-dependent gene expression in brain and female reproductive behavior in rats.

Gonadal steroid hormones act in the brain to elicit changes in gene expression that result in profound effects on behavior and physiology. A variety of in vitro studies indicate that nuclear receptor coactivators are required for efficient transcriptional activity of steroid receptors. Two nuclear receptor coactivators, steroid receptor coactivator-1 (SRC-1) and cAMP response element binding protein-binding protein (CBP), have been shown to act in concert to enhance ER activity in vitro. In the present study, we investigated the function of these important nuclear receptor coactivators in estrogen action in rodent brain. Reduction of SRC-1 and CBP protein in brain disrupted ER-mediated activation of the behaviorally relevant progestin receptor gene. Furthermore, we found that SRC-1 and CBP function in brain to modulate the expression of hormone-dependent female sexual behavior. These findings indicate that these nuclear receptor coactivators function in brain to modulate ER transcriptional activity and the expression of hormone-dependent behavior.

Animals↗
PubMed2002

PIAS3 (protein inhibitor of activated STAT-3) modulates the transcriptional activation mediated by the nuclear receptor coactivator TIF2.

PIAS3, a member of the protein inhibitor of activated STAT family, was found to interact in vivo and in vitro with TIF2, a previously described coactivator for nuclear receptors. The interaction is mediated by two distinct non-contiguous regions of TIF2. We found that TIF2-PIAS3 interaction occurs through a unique domain of PIAS3, very rich in acidic residues and conserved throughout the PIAS family. PIAS3 modulates the ability of TIF2 to mediate ligand-enhanced transcription activation positively or negatively, for different steroid receptors. Taken together, our results indicate a potential role of PIAS3 as transcriptional modulator of TIF2-mediated signalling.

Androgens↗
PubMed2002

ERAP140, a conserved tissue-specific nuclear receptor coactivator.

We report here the identification and characterization of a novel nuclear receptor coactivator, ERAP140. ERAP140 was isolated in a screen for ER alpha-interacting proteins using the ER alpha ligand binding domain as a probe. The ERAP140 protein shares no sequence and has little structural homology with other nuclear receptor cofactors. However, homologues of ERAP140 have been identified in mouse, Drosophila, and Caenorhabditis elegans. The expression of ERAP140 is cell and tissue type specific and is most abundant in the brain, where its expression is restricted to neurons. In addition to interacting with ER alpha, ERAP140 also binds ER beta, TR beta, PPAR gamma, and RAR alpha. ERAP140 interacts with ER alpha via a noncanonical interaction motif. The ER alpha-ERAP140 association can be competed by coactivator NR boxes, indicating ERAP140 binds ER alpha on a surface similar to that of other coactivators. ERAP140 can enhance the transcriptional activities of nuclear receptors with which it interacts. In vivo, ERAP140 is recruited by estrogen-bound ER alpha to the promoter region of endogenous ER alpha target genes. Furthermore, the E(2)-induced recruitment of ERAP140 to the promoter follows a cyclic pattern similar to that of other coactivators. Our results suggest that ERAP140 represents a distinct class of nuclear receptor coactivators that mediates receptor signaling in specific target tissues.

Amino Acid Sequence↗
PubMed2000

Temporal/spatial expression of nuclear receptor coactivators in the mouse lung.

Our laboratory has previously demonstrated that retinoic acid nuclear receptor, thyroid transcription factor-1 (TTF-1), and nuclear receptor coactivators such as cAMP response element binding protein (CREB) binding protein (CBP)/p300 and steroid receptor coactivator-1 (SRC-1) form an enhanceosome on the 5'-enhancer region of the human surfactant protein B gene. Immunohistochemistry was used to identify cells that coexpressed CBP/p300, SRC-1, retinoid X receptor, and TTF-1 in the developing and mature lung. CBP/p300 and SRC-1 were expressed in the adult mouse lung, CBP and p300 being present in both alveolar type I and type II epithelial cells and SRC-1 and TTF-1 being restricted to type II epithelial cells. CBP/p300, SRC-1, and TTF-1 were readily detected in the nuclei of developing respiratory epithelial tubules in fetal mice from embryonic days 10 to 18. CBP/p300 and SRC-1 were also detected in developing mesenchymal cells. These coactivators were coexpressed with TTF-1 and SP-B in human pulmonary adenocarcinoma cells (H441 cells) in vitro. Interaction assays with a two-hybrid reporter analysis demonstrated direct interactions among TTF-1, SRC-1, and CBP/p300 in H441 cells. These findings support a role for retinoic acid receptor and nuclear receptor coactivators in the regulation of SP-B gene expression in the respiratory epithelium.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1999

Nuclear receptor coactivator SRC-1 interacts with the Q-rich subdomain of the AhR and modulates its transactivation potential.

The aryl hydrocarbon receptor (AhR), a soluble cytosolic protein, mediates many of the toxic effects of TCDD and related chemicals. The toxic effects are largely cell, tissue, and promoter context dependent. Although many details of the overall dioxin signal transduction have been elucidated, the transcriptional regulation of dioxin-induced genes like cyp1A1 is not yet completely understood. Previously, we have shown that the co-regulator RIP140 is a potential AhR coactivator. In this report, the role of coactivator, SRC-1, in AhR-mediated transcriptional regulation was examined. SRC-1 increased AhR-mediated, TCDD-dependent reporter gene activity three-fold in Hepa-1 and COS-1 cells. In in vitro interaction assays, SRC-1 was found to interact with AhR but not with ARNT. SRC-1 interacted weakly with AhR in the absence of TCDD and the addition of ligand further increased SRC-1 binding to AhR. Deletional mapping studies of the AhR revealed that SRC-1 binds to the AhR transactivation domain. Finer mapping of the SRC-1-interacting subdomains in the AhR transactivation domain suggested that the Q-rich subdomain was necessary and sufficient for interaction, similar to that seen with RIP140. Using GFP-tagged constructs, SRC-1 was shown to interact with AhR in cells. Unlike RIP140, LXXLL motifs in SRC-1 were necessary for interaction with AhR in vitro and for coactivation in Hepa-1 cells. The recruitment of certain coactivators by a variety of receptors suggests possible common coactivator pools and competition among receptors for limiting coactivators. Examination of the role of SRC-1 in AhR/ARNT transactivation in ARNT-deficient mutant Hepa-1 c4 cells demonstrates that the AhR transactivation domain is sufficient for enhanced coactivation mediated by SRC-1 in the presence of a transactivation domain deleted ARNT protein.

Adaptor Proteins, Signal Transducing↗
PubMed2002

The nuclear receptor coactivators p300/CBP/cointegrator-associated protein (p/CIP) and transcription intermediary factor 2 (TIF2) differentially regulate PKA-stimulated transcriptional activity of steroidogenic factor 1.

Steroidogenic factor-1 (SF-1) is a member of the nuclear receptor superfamily that plays essential roles in the development of endocrine organs. Steroid receptor coactivator 1 and transcription intermediary factor 2 (TIF2) belong to the p160 coactivator family that mediates transcriptional activation by several nuclear receptors, including SF-1. Here, it is reported that another of the p160 coactivators, p/CIP, interacts with SF-1 through the activation function-2 domain. Both p300/CBP/cointegrator-associated protein (p/CIP) and TIF2 potentiated SF-1-mediated transcription from two reporter gene constructs in transfected nonsteroidogenic COS-1 cells and in adrenocortical Y1 cells. PKA was shown to stimulate SF-1 transcriptional activity, and coexpression of p/CIP together with the PKA catalytic subunit stimulated SF-1-mediated transactivation even further. In contrast, PKA catalytic subunit overexpression impaired the ability of TIF2 to potentiate SF-1-dependent transcription. Activation of PKA also inhibited the TIF2-mediated coactivation of other nuclear receptors such as PPAR alpha/-gamma and liver X receptor-alpha. The TIF2 mRNA levels were not affected by PKA, but instead we found that PKA activation led to a decrease in the levels of TIF2 protein. Moreover, the C-terminal activation domain 2 of TIF2 was required for the inhibitory effect of PKA, suggesting that this region is the target for the PKA-mediated down-regulation. Thus, in contrast to the regulation of p/CIP and steroid receptor coactivator 1, we suggest that activation of PKA leads to selective down-regulation of TIF2 and subsequently repression of TIF2 coactivator function.

Animals↗
PubMed2003

Nuclear receptor coactivator function in reproductive physiology and behavior.

Gonadal steroid hormones act throughout the body to elicit changes in gene expression that result in profound effects on reproductive physiology and behavior. Steroid hormones exert many of these effects by binding to their respective intracellular receptors, which are members of a nuclear receptor superfamily of transcriptional activators. A variety of in vitro studies indicate that nuclear receptor coactivators are required for efficient transcriptional activity of steroid receptors. Many of these coactivators are found in a variety of steroid hormone-responsive reproductive tissues, including the reproductive tract, mammary gland, and brain. While many nuclear receptor coactivators have been investigated in vitro, we are only now beginning to understand their function in reproductive physiology and behavior. In this review, we discuss the general mechanisms of action of nuclear receptor coactivators in steroid-dependent gene transcription. We then review some recent and exciting findings on the function of nuclear receptor coactivators in steroid-dependent brain development and reproductive physiology and behavior.

Animals↗
PubMed2005

Activation of nuclear receptor coactivator PGC-1alpha by arginine methylation.

Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), a tissue-specific and inducible transcriptional coactivator for several nuclear receptors, plays a key role in energy metabolism. We report here that PGC-1alpha coactivator activity is potentiated by arginine methylation by protein arginine methyltransferase 1 (PRMT1), another nuclear receptor coactivator. Mutation of three substrate arginines in the C-terminal region of PGC-1alpha abolished the cooperative coactivator function of PGC-1alpha and PRMT1, and compromised the ability of PGC-1alpha to induce endogenous target genes. Finally, endogenous PRMT1 contributes to PGC-1alpha coactivator activity, and to the induction of genes important for mitochondrial biogenesis.

Animals↗
PubMed2000

Involvement of nuclear receptor coactivator SRC-1 in estrogen-dependent cell growth of MCF-7 cells.

Steroid hormones regulate cell growth and function through the transcriptional control of target genes by their cognate nuclear receptors. These receptors bind to ligands and associate with transcriptional cofactors to stimulate transcription. SRC-1, one of the nuclear receptor coactivators, is known to interact with nuclear receptors and enhance transactivation function in a ligand-dependent manner. In this study, to assess the function of SRC-1 in cell growth regulated by nuclear receptor ligands, we established a stable transformant cell line overexpressing human SRC-1 and studied the action of 17beta-estradiol (E(2)) on cell growth as well as the expression of E(2)-responsive genes in MCF-7 cells. We found that SRC-1 overexpression potentiates cell growth stimulated by E(2) in accordance with enhancement of transcriptional activation of exogenous and endogenous E(2)-responsive genes. These findings clearly indicate the importance of nuclear receptor coactivators for the activities of steroid/lipophilic vitamins in cell growth and gene expression.

Adenocarcinoma↗
PubMed2005

Synovial sarcoma translocation (SYT) encodes a nuclear receptor coactivator.

We previously cloned and characterized a novel RNA-binding motif-containing coactivator, named coactivator activator (CoAA), as a thyroid hormone receptor-binding protein-interacting protein using a Sos-Ras yeast two-hybrid screening system. A database search revealed that CoAA is identical with synovial sarcoma translocation (SYT)-interacting protein. Thus, we hypothesized that SYT could also function as a coactivator. Subsequently, we isolated a cDNA encoding a larger isoform of SYT, SYT-long (SYT-L), from the brain and liver total RNA using RT-PCR. SYT-L possesses an additional 31 amino acids in its C terminus compared with SYT, suggesting that these two SYT isoforms may be expressed from two mRNAs produced by alternative splicing of a transcript from a single gene. By Northern blot analysis, we found that SYT-L mRNA is expressed in several human embryonic tissues, such as the brain, liver, and kidney. However, we could not detect SYT-L in adult tissues. Glutathione-S-transferase pull-down studies showed that SYT binds to the C-terminus of CoAA, but not to the coactivator modulator. Both isoforms of SYT function as transcriptional coactivators of nuclear hormone receptors in a ligand- and dose-dependent manner in CV-1, COS-1, and JEG-3 cells. However, the pattern of transactivation was different between SYT and SYT-L among these cells. SYT synergistically activates transcription with CoAA. In addition, SYT activates transcription through activator protein-1, suggesting that SYT may function as a general coactivator. These results indicate that SYT activates transcription, possibly through CoAA, to interact with the histone acetyltransferase complex.

Age Factors↗
PubMed2004

Overexpression of the nuclear receptor coactivator AIB1 (SRC-3) during progression of pancreatic adenocarcinoma.

PURPOSE: The nuclear receptor coactivator amplified in breast cancer 1 (AIB1) was found to be amplified and overexpressed in breast and some other epithelial tumors. We have reported that expression of AIB1 is rate limiting for growth factor, as well as hormone signaling. Here, we assess the involvement of AIB1 in the development of pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: We investigated expression levels of AIB1 protein and mRNA in pancreatic cancer cell lines and in a series of archival pancreatic adenocarcinoma (n=78), pancreatic intraepithelial neoplasia (n=93), pancreatitis (n=28), and normal pancreas tissues (n=52). We also determined AIB1 gene copy numbers by fluorescence in situ hybridization in a subset of cases. RESULTS: In normal pancreas ducts, we rarely found detectable levels of AIB1 mRNA or protein (<6% of the samples). In pancreatitis and low-grade intraepithelial neoplasia, we found an increased frequency of AIB1 expression (>14 and >23%, respectively) relative to normal tissues (P < 0.01). Adenocarcinoma, as well as high-grade intraepithelial neoplasia, showed increased levels as well as the highest frequency of AIB1 expression with >65% of samples positive for mRNA and protein (P < 0.0001 relative to the other groups). An increased copy number of the AIB1 gene, observed in 37% of cancers, may account for a portion of the increase in expression. CONCLUSIONS: AIB1 overexpression is frequent in pancreatic adenocarcinoma and its precursor lesions. On the basis of its rate-limiting role for the modulation of growth factor signals, we propose a major role of AIB1 in the multistage progression of pancreatic cancer.

Adenocarcinoma↗