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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroid receptors activate transcription in yeast cells via interactions with endogenous coactivators and/or basal factors. We examined the effects of mutations in the ligand binding domain on the transcriptional activity of ERalpha in yeast. Our results show that mutations in Helix 3 (K366A) and Helix 12 (M547A, L548A) disrupt transcriptional activity of ERalpha in yeast, as previously observed in mammalian cells. However, replacement of a conserved tyrosine residue in Helix 12 with alanine or aspartate (Y541A and Y541D), which renders ERalpha constitutively active in mammalian cells, had only a weak stimulatory effect on ligand-independent reporter activation by ERalpha in yeast. Two-hybrid interaction experiments revealed that a Y541A mutant expressed in yeast was capable of ligand-independent binding to a mammalian coactivator, suggesting that there is a subtle difference in how this mutant interacts with mammalian and yeast cofactors. We also show that the ligand-dependent activities of ERalpha and progesterone receptor (PR) in yeast cells were strongly enhanced by the human p160 protein steroid receptor coactivator (SRC1), but not by CREB-Binding Protein (CBP) or the p300/CBP associated factor (P/CAF). Although the SRC1 activation domains AD1 and AD2 are functional in yeast, deletion of these sequences only partially impaired SRC1 coactivator function in this organism; this is in contrast to similar experiments in mammalian cells. Thus SRC1 sequences involved in recruitment of CBP/p300 and Co-Activator-Associated Arginine Methyltransferase (CARM-1) in mammalian cells are not essential for its function in yeast, suggesting that SRC1 operates via distinct mechanisms in yeast and mammalian cells.
J Mol Endocrinol 2003 Jun
PMID:Transcriptional activation by estrogen receptor (ERalpha) and steroid receptor coactivator (SRC1) involves distinct mechanisms in yeast and mammalian cells. 1279 Aug 9

The p160 steroid receptor coactivator (SRC) gene family contains three homologous members, which serve as transcriptional coactivators for nuclear receptors and certain other transcription factors. These coactivators interact with ligand-bound nuclear receptors to recruit histone acetyltransferases and methyltransferases to specific enhancer/promotor regions, which facilitates chromatin remodeling, assembly of general transcription factors, and transcription of target genes. This minireview summarizes our current knowledge about the molecular structures, molecular mechanisms, temporal and spatial expression patterns, and biological functions of the SRC family. In particular, this article highlights the roles of SRC-1 (NCoA-1), SRC-2 (GRIP1, TIF2, or NCoA-2) and SRC-3 (p/CIP, RAC3, ACTR, AIB1, or TRAM-1) in development, organ function, endocrine regulation, and nuclear receptor function, which are defined by characterization of the genetically manipulated animal models. Furthermore, this article also reviews our current understanding of the role of SRC-3 in breast cancer and discusses possible mechanisms for functional specificity and redundancy among SRC family members.
Mol Endocrinol 2003 Sep
PMID:Review of the in vivo functions of the p160 steroid receptor coactivator family. 1280 12

Cell programs such as proliferation and differentiation involve the sequential activation and repression of gene expression. Vitamin D, via its active metabolite 1,25-dihydroxyvitamin D [1,25-(OH)2D3)], controls the proliferation and differentiation of a number of cell types, including keratinocytes, by directly regulating transcription. Two classes of coactivators, the vitamin D receptor (VDR)-interacting proteins (DRIP/mediator) and the p160 steroid receptor coactivator family (SRC/p160), control the actions of nuclear hormone receptors, including the VDR. However, the relationship between these two classes of coactivators is not clear. Using glutathione-S-transferase-VDR affinity beads, we have identified the DRIP/mediator complex as the major VDR binding complex in proliferating keratinocytes. After the cells differentiated, members of the SRC/p160 family were identified in the complex but not major DRIP subunits. Both DRIP and SRC proteins were expressed in keratinocytes. DRIP205 expression decreased during differentiation, although SRC-3 levels increased. Both DRIP205 and SRC-3 potentiated vitamin D-induced transcription in proliferating cells, but during differentiation, DRIP205 was no longer effective. These results indicate that these two distinct coactivators are sequentially involved in vitamin D regulation of gene transcription during keratinocyte differentiation, suggesting that these coactivators are part of the means by which the temporal sequence of gene expression is regulated during the differentiation process.
Mol Endocrinol 2003 Nov
PMID:Two distinct coactivators, DRIP/mediator and SRC/p160, are differentially involved in vitamin D receptor transactivation during keratinocyte differentiation. 1289 81

The orphan nuclear receptor steroidogenic factor-1 (SF-1) plays pivotal roles in the development and function of steroidogenic organs. It transcriptionally regulates an array of factors required for biosynthesis of steroid hormones and is also necessary for the expression of genes in the pituitary and the male reproductive tract. Here we describe the identification of a novel zinc finger protein that modifies the transcriptional potential of SF-1. This factor, which we call Zip67 (zinc finger protein 67 kDa), was cloned through a two-hybrid screen of a human testis cDNA library using the C-terminal part of SF-1 as the bait. Transient transfection experiments demonstrated that Zip67 represses SF-1-dependent transcription in the context of both multimerized SF-1-binding sites and natural SF-1-inducible promoters. The interaction between Zip67 and SF-1 was dependent on an intact activation function-2 domain of SF-1, and we propose a mechanism whereby Zip67 represses transcription through competition with p160 coactivators for binding to SF-1. Zip67 was detected in SF-1 expressing tissues such as testis, adrenal, ovary and spleen in addition to other tissues. In line with the broader expression pattern, we found that Zip67 also affected transcription mediated by several other nuclear receptors. In conclusion, we have isolated a novel zinc-finger protein that influences gene activation through interaction with the functionally important activation function-2 domain of nuclear receptors.
Mol Endocrinol 2003 Nov
PMID:Cloning and characterization of a novel zinc finger protein that modulates the transcriptional activity of nuclear receptors. 1292 Feb 34

We developed a molecular genetic model to investigate glucocorticoid receptor (GR) signaling in human bronchial epithelial cells in response to the therapeutic steroid budesonide. Based on a genetic selection scheme using the human Chago K1 cell line and integrated copies of a glucocorticoid-responsive herpes simplex virus thymidine kinase gene and a green fluorescent protein gene, we isolated five Chago K1 variants that grew in media containing budesonide and ganciclovir. Three spontaneous budesonide-resistant subclones were found to express low levels of GR, whereas two mutants isolated from ethylmethane sulfonate-treated cultures contained normal levels of GR protein. Analysis of the GR coding sequence in the budesonide-resistant subclone Ch-BdE5 identified a novel Val to Met mutation at amino acid position 575 (GRV575M) which caused an 80% decrease in transcriptional regulatory functions with only a minimal effect on ligand binding activity. Homology modeling of the GR structure in this region of the hormone binding domain and molecular dynamic simulations suggested that the GRV575M mutation would have a decreased affinity for the LXXLL motif of p160 coactivators. To test this prediction, we performed transactivation and glutathione-S-transferase pull-down assays using the p160 coactivator glucocorticoid interacting protein 1 (GRIP1)/transcriptional intermediary factor 2 and found that GRV575M transcriptional activity was not enhanced by GRIP1 in transfected cells nor was it able to bind GRIP1 in vitro. Identification of the novel GRV575M variant in human bronchial epithelial cells using a molecular genetic selection scheme suggests that functional assays performed in relevant cell types could identify subtle defects in GR signaling that contribute to reduced steroid sensitivities in vivo.
Mol Endocrinol 2003 Dec
PMID:Identification of a novel glucocorticoid receptor mutation in budesonide-resistant human bronchial epithelial cells. 1292 Feb 35

Hormone-activated nuclear receptors (NR) bind to the promoters of their target genes and recruit coactivator proteins to help activate transcription. The p160 coactivators bind directly to activated NRs and recruit secondary coactivators CBP/p300 with protein acetyltransferase activity and CARM1 with protein methyltransferase activity. To further investigate the components of the p160 coactivator complex and their mechanisms of action, we have used two guiding assumptions. First, the coactivators constitute a signal transduction pathway that convey the signal from DNA-bound NRs to the transcription machinery. Second, each coactivator has signal input and signal output domains that facilitate signal transduction. These assumptions were used to address the mechanism by which CARM1 and the N-terminal region of p160 coactivators transmit activating signals to the transcription machinery. The p160-binding activity of CARM1 is in the same centrally located structural domain as the methyltransferase activity; the p160-binding domain anchors CARM1 to the target gene promoter and thereby serves as its signal input domain. CARM1 has two signal output mechanisms: the protein methyltransferase activity, which methylates histones and other proteins in the transcription initiation complex; and a strong autonomous activation function in the C-terminal region. We identified a protein, CCCP, which binds to the C-terminal region of CARM1 and cooperates synergistically with CARM1 to enhance NR function. We also defined the N-terminal region of p160 coactivators as another signal output domain, which binds a novel coactivator called coiled-coil coactivator (CoCoA). CoCoA acts synergistically with p160 coactivators to enhance NR function.
J Steroid Biochem Mol Biol 2003 Jun
PMID:The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators. 1294 98

The nucleus contains different sets of functional compartments often called "speckles". The splicing factor compartment (SFC) has been speculated to consist of SFs and transcription factors, which thus make transcription-splicing coupling possible at the periphery of SFC. Androgen receptor (AR), as well as glucocorticoid receptor (GR), is unique since most, if not all, of its activities are mediated via the constitutive activity of the activation function-1 (AF-1) function. Transcriptionally active AR produces 250-400 subnuclear fine speckles11 shared with GR or estrogen receptor (ER), which colocalize with chiefly activation function-2 (AF-2)-interacting p160 family- or CBP-related speckles. We herein report the isolation of ANT-1 (AR N-terminal domain (NTD) transactivating protein-1) enhancing autonomous AF-1 transactivation function of AR or GR, but not of estrogen receptor alpha (ERalpha). The ANT-1 was identical to a binding protein of human splicing factor U5 snRNP (U5 snRNP-associated protein). ANT-1 was compartmentalized into 15-20 coarse SFC speckles which were spatially distinct from but surrounded by the AR compartments. Our results suggest that ANT-1 may play a key role in the molecular interaction between two spatially distinct subnuclear compartments in a receptor-specific fashion, and thereby induce the strong autonomous transactivation functions either of AR- or GR-AF-1.
J Steroid Biochem Mol Biol 2003 Jun
PMID:Activation function-1 domain of androgen receptor contributes to the interaction between two distinct subnuclear compartments. 1294 5

Using cDNA array-based gene expression profiling, we previously found reduced expression of the Caspase-5 gene in highly metastatic subpopulations of a lung cancer cell line. The Caspase-5 gene contained poly(A) repeats in its coding region, an area that has been reported to be mutated in both endometrial and gastrointestinal tumors displaying evidence of microsatellite instability. In order to determine the contribution of Caspase-5 gene inactivation to lung cancer development and progression, the mutational status of the Caspase-5 poly(A) tract in 30 primary lung cancers with distant metastasis and 30 lung cancer cell lines was determined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing. Three somatic mutations of the Caspase-5 gene were found in two out of 30 lung cancer tissues, although no mutations were found in other genes that also contain small nucleotide repeats, such as hMSH3, hMSH6 and BAX. The results of the present study, combined with our prior cDNA array-based gene expression profiling data, suggest that Caspase-5 might be a suppressor gene of highly metastatic potential in lung cancer.
Int J Mol Med 2003 Oct
PMID:Somatic mutation of the Caspase-5 gene in human lung cancer. 1296 16

Steroid receptor coactivator 3 (SRC-3/p/CIP/AIB1/ACTR/RAC3/TRAM-1) is a member of the p160 family of nuclear receptor coactivators, which includes SRC-1 (NCoA-1) and SRC-2 (TIF2/GRIP1/NCoA2). Previous studies indicate that SRC-3 is required for normal animal growth and is often amplified or overexpressed in many cancers, including breast and prostate cancers. However, the mechanisms of SRC-3-mediated growth regulation remain unclear. In this study, we show that overexpression of SRC-3 stimulates cell growth to increase cell size in prostate cancer cell lines. Furthermore, our results indicate that overexpression of SRC-3 can modulate the AKT signaling pathway in a steroid-independent manner, which results in the activation of AKT/mTOR signaling concomitant with an increase in cell size. In contrast, down-regulation of SRC-3 expression in cells by small interfering RNA decreases cell growth, leading to a smaller cell size. Similarly, in SRC-3 null mutant mice, AKT signaling is down-regulated in normally SRC-3-expressing tissues. Taken together, these results suggest that SRC-3 is an important modulator for mammalian cell growth.
Mol Cell Biol 2003 Nov
PMID:Role of the steroid receptor coactivator SRC-3 in cell growth. 1456 19

Aryl hydrocarbon receptor (AHR) is a transcription factor whose activity is regulated by environmental agents, including several carcinogenic agonists. We measured recruitment of AHR and associated proteins to the human cytochrome P4501A1 gene promoter in vivo. Upon treatment with the agonist beta-naphthoflavone, AHR is rapidly associated with the promoter and recruits the three members of the p160 family of coactivators as well as the p300 histone acetyltransferase, leading to recruitment of RNA polymerase II (Pol II) and induction of gene transcription. AHR, coactivators, and Pol II cycle on and off the promoter, with a period of approximately 60 min. In contrast, the chemopreventative AHR ligand 3,3'-diindolylmethane promotes AHR nuclear translocation and p160 coactivator recruitment but, remarkably, fails to recruit Pol II or cause histone acetylation. This novel mechanism of receptor antagonism may account for the antitumor properties of chemopreventative compounds targeting the AHR.
Mol Cell Biol 2003 Nov
PMID:Agonist and chemopreventative ligands induce differential transcriptional cofactor recruitment by aryl hydrocarbon receptor. 1456 34


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