Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear receptors regulate transcription by binding to specific DNA response elements of target genes. Herein, we report the molecular cloning and characterization of a novel Xenopus cDNA encoding a transcription coactivator xSRC-3 by using retinoid X receptor (RXR) as a bait in the yeast two-hybrid screening. It belongs to a growing coactivator family that includes a steroid receptor coactivator amplified in breast cancer (AIB1), p300/ CREB-binding protein (CBP)-interacting protein (p/ CIP), and transcriptional intermediate factor 2 (TIF2). It also interacts with a series of nuclear receptors including retinoic acid receptor (RAR), thyroid hormone receptor (TR), and orphan nuclear receptors [hepatocyte nuclear receptor 4 (HNF4) and constitutive androstane receptor (CAR)]. However, it does not interact with small heterodimer partner (SHP), an orphan nuclear receptor known to antagonize ligand-dependent transactivation of other nuclear receptors. In CV-1 cells, cotransfection of xSRC-3 differentially stimulates ligand-induced transactivation of RXR, TR, and RAR in a dose-dependent manner. Interestingly, xSRC-3 is highly expressed in adult liver and early stages of oocyte development, suggesting that studies of xSRC-3 may lead to better understanding of the roles nuclear receptors play in oocyte development as well as liver-specific gene expression.
Mol Endocrinol 1998 Jul
PMID:Molecular cloning of xSRC-3, a novel transcription coactivator from Xenopus, that is related to AIB1, p/CIP, and TIF2. 965 7

Gene transcription is often regulated by small ligands, enabling cells to respond to external and metabolic stimuli. Of particular interest are the mechanisms by which hydrophobic hormones modulate the transcriptional activities of proteins of the nuclear receptor superfamily. It was previously shown that, in the absence of ligand, the retinoid X receptor (RXRalpha) forms tetramers with a high affinity and a pronounced positive co-operativity such that tetramers become the receptor's predominant species tat concentrations as low as 60-70 nM. It was shown further that while RXR tetramers are remarkably stable in the absence of ligand, ligand-binding induces their rapid dissociation into smaller species, dimers and monomers. Here, the functional consequences of the self-association properties of RXR were studied by examining two point mutants of RXR that displayed aberrant oligomerization behaviors. One mutant, mRXRalpha-R321A, was found to form tetramers with a wild-type affinity, but these tetramers failed to dissociate upon ligand-binding. This mutant was found to be impaired in its ability to associate with the nuclear receptor co-activator p/CIP and to activate transcription in response to the RXR ligand 9-cis-retinoic acid. The other mutant, mRXRalpha-F318A, self-associated into dimers with a wild-type affinity, but was unable to form tetramers. This mutant displayed substantial transcriptional activity even in the absence of ligand. We previously proposed, based on in vitro studies that RXR acts as an auto-silencer by sequestering itself into tetramers, and that an important role for the ligand in activating this receptor is to release active species, dimers and monomers, from the transcriptionally inactive tetrameric pool. The observations reported here provide in-cell evidence in support of this model and indicate that ligand induced dissociation of tetramers is the first step in signalling by RXR.
J Mol Biol 1998 Nov 20
PMID:Auto-silencing by the retinoid X receptor. 981 39

The nuclear vitamin D receptor (VDR) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor. A family of cotranscriptional activators (SRC-1, TIF2, and AIB-1) interacts with and activates the transactivation function of nuclear receptors in a ligand-dependent way. We examined interaction of VDR with these coactivators that was induced by several vitamin D analogs, since they exert differential subsets of the biological action of vitamin D through unknown mechanisms. Unlike other vitamin D analogs tested, OCT (22-oxa-1alpha,25-dihydroxyvitamin D3) induced interaction of VDR with TIF2 but not with SRC-1 or AIB-1. Consistent with these interactions, only TIF2 was able to potentiate the transactivation function of VDR bound to OCT. Thus, the present findings suggest that the structure of VDR is altered in a vitamin D analog-specific way, resulting in selective interactions of VDR with coactivators. Such selective interaction of coactivators with VDR may specify the array of biological actions of a vitamin D analog like OCT, possibly through activating a particular set of target gene promoters.
Mol Cell Biol 1999 Feb
PMID:Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog. 989 Oct 40

The tumor suppressor protein p53 exerts its cell cycle-regulatory effects through its ability to function as a sequence-specific DNA-binding transcription factor. Herein, we show that p53 physically interacts with specific subregions of steroid receptor coactivator-1 (SRC-1) and its family members, p/CIP (p300/CBP interacting protein), xSRC-3, and AIB1 (amplified in breast cancer), originally isolated as transcription coactivators of nuclear receptors, as demonstrated by the yeast and mammalian two-hybrid tests as well as glutathione S-transferase pull-down assays. Interestingly, cotransfection of HeLa cells with SRC-1- or p/CIP expression vector potentiated the p53-mediated transactivation, whereas AIB1 and xSRC-3 were repressive. All of these SRC-1 members, however, similarly stimulated transactivation mediated by nuclear receptors and AP-1, as previously described. These results suggest that SRC-1 and its family members may differentially modulate the p53 transactivation in vivo.
Mol Endocrinol 1999 Nov
PMID:Steroid receptor coactivator-1 and its family members differentially regulate transactivation by the tumor suppressor protein p53. 1055 85

In this report, we demonstrate that, in contrast to most previously characterized nuclear receptors, hERR1 and hERR2 (human estrogen receptor-related protein 1 and -2) are constitutive activators of the classic estrogen response element (ERE) as well as the palindromic thyroid hormone response element (TRE(pal)) but not the glucocorticoid response element (GRE). This intrinsically activated state of hERR1 and hERR2 resides in the ligand-binding domains of the two genes and is transferable to a heterologous receptor. In addition, we show that members of the p160 family of nuclear receptor coactivators, ACTR (activator of thyroid and retinoic acid receptors), GRIP1 (glucocorticoid receptor interacting protein 1), and SRC-1 (steroid receptor coactivator 1), potentiate the transcriptional activity by hERR1 and hERR2 in mammalian cells, and that both orphan receptors bind the coactivators in a ligand-independent manner. Together, these results suggest that hERR1 and hERR2 activate gene transcription through a mechanism different from most of the previously characterized steroid hormone receptors.
Mol Endocrinol 1999 Dec
PMID:Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2. 1059 88

In order to approach the molecular basis of the tissue-specific agonistic activity of antioestrogens, we have compared, at the mRNA level, the expression of various transcriptional cofactors (activators or repressors) of estrogen receptors in different breast (MCF7, ZR75-1, T47D, MDA-MB231) and endometrial (Ishikawa, RL-95-2 and HEC1A) human cancer cell lines. We showed that for SRC-1, CBP, TIF1alpha, RIP140, N-CoR, and SMRT, no significant differences in the expression levels were observed between breast and endometrial cells. For TIF1alpha mRNA, both isoforms were also detected at similar levels in all the cells tested. By contrast, over-expression of AIB1 mRNA was observed in MCF7 cells, but not in other breast or endometrial cells, irrespective of their ER-status. We then used protein-protein interaction assay (far-Western blot) to confirm the increased expression of at least one of the p160 proteins in MCF7 cells. Finally, we demonstrated that RIP140 mRNA is directly induced by estrogens in ER-positive MCF7 breast cancer cell lines but not in Ishikawa endometrial cells. Together these results indicate that some differences exist between breast and endometrial cancer cell lines at the level of estrogen receptor transcription cofactor expression.
Mol Cell Endocrinol 1999 Oct 25
PMID:Estrogen receptor cofactors expression in breast and endometrial human cancer cells. 1061 26

Transforming growth factor beta (TGF-beta) plays important roles in the regulation of proliferation, differentiation, apoptosis, and carcinogenesis. To identify genes responsible for maintaining the phenotype induced by TGF-beta, we performed a retrovirus-mediated gene trap screening designed to isolate TGF-beta-responsive genes in human lung carcinoma cell line A549. After screening 249 trap lines, 21 were found to express the reporter beta-galactosidase gene in a TGF-beta-responsive manner. Interestingly, in large proportions of these trap lines, the reporter gene was responsive also to phorbol ester and was suppressed by gamma interferon. Fragments of all these trapped genes were recovered by 5'- and 3'-rapid amplification of cDNA ends (RACE), and in 15 out of 21 cases (71%), the TGF-beta responsiveness of the endogenous genes was confirmed by RNA blot hybridization. In at least five cases, the TGF-beta-induced upregulation was found to be cycloheximide resistant, suggesting the roles of the genes in the TGF-beta-induced primary responses. Sequence analyses revealed that 43% (9 of 21) of the trapped genes were novel and that the remainder included genes previously reported to be upregulated by TGF-beta, such as epidermal growth factor receptor and beta1 integrin, documenting the validity of this approach. Other known genes include the ones encoding the proteins associated with cell proliferation (ribosomal proteins S15a, hNRP/NAP-1, and lipocortin II), focal adhesions (paxillin), and transcriptional regulation (thyroid hormone receptor activator molecule 1 [TRAM-1]).
Mol Cell Biol 2000 May
PMID:Identification of a series of transforming growth factor beta-responsive genes by retrovirus-mediated gene trap screening. 1075 10

The increasing number of factors to be taken into account in the oestrogen transcriptional process has created a need to develop a rapid screening method to evaluate their role in physiology and pathology. Molecular biology techniques enable gene expression studies at the mRNA level with small amounts of tissues. We therefore developed a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) technique using fluorescent oligonucleotides to analyse simultaneously a large panel of interrelated genes involved in the oestrogen transcriptional pathway using a moderately expressed housekeeping gene, the hypoxanthine phosphoribosyltransferase gene (HPRT), as the reference gene. Expression levels of oestrogen receptors (ERalpha, ERbeta), cofactors AIB1, RIP140, SMRT and the Fas-associated protein-tyrosine phophatase-1 (FAP-1) genes were evaluated in breast, endometrial and ovarian cancer cell lines and in three ERalpha-positive and three ERalpha-negative breast cancer tumours. This technique provides a rapid and reliable way to quantitate simultaneously numerous mRNAs of genes involved in the oestrogen pathway from small amounts of tissues.
J Mol Endocrinol 2000 Jun
PMID:Semiquantitative reverse transcription-polymerase chain reaction to evaluate the expression patterns of genes involved in the oestrogen pathway. 1082 36

The state of chromatin (the packaging of DNA in eukaryotes) has long been recognized to have major effects on levels of gene expression, and numerous chromatin-altering strategies-including ATP-dependent remodeling and histone modification-are employed in the cell to bring about transcriptional regulation. Of these, histone acetylation is one of the best characterized, as recent years have seen the identification and further study of many histone acetyltransferase (HAT) proteins and their associated complexes. Interestingly, most of these proteins were previously shown to have coactivator or other transcription-related functions. Confirmed and putative HAT proteins have been identified from various organisms from yeast to humans, and they include Gcn5-related N-acetyltransferase (GNAT) superfamily members Gcn5, PCAF, Elp3, Hpa2, and Hat1: MYST proteins Sas2, Sas3, Esa1, MOF, Tip60, MOZ, MORF, and HBO1; global coactivators p300 and CREB-binding protein; nuclear receptor coactivators SRC-1, ACTR, and TIF2; TATA-binding protein-associated factor TAF(II)250 and its homologs; and subunits of RNA polymerase III general factor TFIIIC. The acetylation and transcriptional functions of these HATs and the native complexes containing them (such as yeast SAGA, NuA4, and possibly analogous human complexes) are discussed. In addition, some of these HATs are also known to modify certain nonhistone transcription-related proteins, including high-mobility-group chromatin proteins, activators such as p53, coactivators, and general factors. Thus, we also detail these known factor acetyltransferase (FAT) substrates and the demonstrated or potential roles of their acetylation in transcriptional processes.
Microbiol Mol Biol Rev 2000 Jun
PMID:Acetylation of histones and transcription-related factors. 1083 22

Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.
Mol Cell Biol 2000 Jul
PMID:AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. 1086 61


1 2 3 4 5 6 7 8 9 10 Next >>