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

The silent mating-type loci of Saccharomyces cerevisiae, HML and HMR, are flanked by transcriptional silencers that have ARS activity (i.e., they function as replication origins when in plasmids). To test whether these ARS elements are chromosomal origins, we mapped origins near HML (close to the left telomere of chromosome III). Our results indicate that the HML-associated ARS elements either do not function as chromosomal replication origins or do so at a frequency below our detection level, suggesting that replication from a silencer-associated origin in each S phase is not essential for the maintenance of transcriptional repression at HML. Our results also imply that the ability of a DNA fragment to function as an ARS element in a plasmid does not ensure its ability to function as an efficient chromosomal replication origin. Telomere proximity is not responsible for inactivating these ARS elements, because they are not detectably functional as chromosomal origins even in genetically modified strains in which they are far from the telomere.
Mol Cell Biol 1991 Oct
PMID:Evidence suggesting that the ARS elements associated with silencers of the yeast mating-type locus HML do not function as chromosomal DNA replication origins. 192 50

Copies of the mating-type genes are present at three loci on chromosome III of the yeast Saccharomyces cerevisiae. The genes at the MAT locus are transcribed, whereas the identical genes at the silent loci, HML and HMR, are not transcribed. Several genes, including the four SIR genes, and two sites, HMR-E and HMR-I, are required for repression of transcription at the HMR locus. Three elements have been implicated in the function of the HMR-E silencer: a binding site for the RAP1 protein, a binding site for the ABF1 protein, and an 11-bp consensus sequence common to nearly all autonomously replicating sequence (ARS) elements (putative origins of DNA replication). RAP1 and ABF1 binding sites of different sequence than those found at HMR-E were joined with an 11-bp ARS consensus sequence to form a synthetic silencer. The synthetic silencer was able to repress transcription of the HMRa1 gene, confirming that binding sites for RAP1 and ABF1 and the 11-bp ARS consensus sequence were the functional components of the silencer in vivo. Mutations in the ABF1 binding site or in the ARS consensus sequence of the synthetic silencer caused nearly complete derepression of transcription at HMR. The ARS consensus sequence mutation also eliminated the ARS activity of the synthetic silencer. These data suggested that replication initiation at the HMR-E silencer was required for establishment of the repressed state at the HMR locus.
Mol Cell Biol 1991 Nov
PMID:A synthetic silencer mediates SIR-dependent functions in Saccharomyces cerevisiae. 192 68

We and others have previously reported that transforming growth factor-alpha (TGF alpha) expression is hormonally responsive and its expression is coregulated with that of its receptor [the epidermal growth factor (EGF) receptor]. The 5'-flanking region of the TGF alpha gene was characterized to determine whether it could confer hormone responsiveness to a reporter gene (luciferase) in human mammary carcinoma cells (MDA468). This segment of the gene is GC rich and contains an element strikingly similar to the core element of the EGF receptor gene that has been shown to mediate both basal and hormone-stimulated expression of the EGF receptor. We now report that a 313-basepair (bp) proximal element of the TGF alpha 5'-flanking region (-373 to -59 relative to the TGF alpha translation start codon) is capable of conferring responses to phorbol ester and EGF. This gene segment does not contain the EGF receptor gene homolog or potential AP-2-binding sites, suggesting that these elements are not necessary for basal and EGF- or phorbol ester-responsive TGF alpha gene expression. This 313-bp proximal element also confers proper transcriptional initiation to the chimeric TGF alpha-luciferase reporter construct, indicating it is the TGF alpha promoter. A 1.1-kilobase segment of the TGF alpha 5'-flanking region also confers retinoic acid, thyroid hormone, and glucocorticoid responsiveness despite the absence of recognizable steroid hormone receptor-binding sites. These hormones stimulate reporter expression 1.5- to 2-fold in a dose-dependent manner. Extension of the 5'-flanking region to -3500 results in marked suppression of reporter gene expression. These results indicate that the TGF alpha gene 5'-flanking sequence contains the elements responsible for hormonal responsiveness of this gene and that these elements are distinct from those that regulate the expression of the EGF receptor gene.
Mol Endocrinol 1991 Apr
PMID:Transcriptional regulation of the human transforming growth factor-alpha gene. 192 84

The antirheumatic gold salt aurothiomalate (AuTM) has cellular actions that are consistent with modulation of gene expression. We have tested the hypothesis that an important mode of action of AuTM is inhibition of binding of certain transcription factors to regulatory elements in DNA. The chemistry of transcription factors containing the zinc finger motif makes them candidates for such an interaction with AuTM. In this regard, the interaction of a steroid hormone receptor, the progesterone receptor (PR), with its DNA response element (PRE) was chosen as a suitable model. Nuclear extracts of T-47D human breast cancer cells rich in PR were incubated with radiolabeled PRE, and binding was determined by gel retardation assay. Preincubation of nuclear extract with AuTM caused a concentration-dependent inhibition of binding of PR to PRE (IC50, approximately 3 microM). Other metal ions inhibited binding at higher concentrations, in a rank order correlating with their binding affinity for thiols. Thiomalic acid had no effect in the absence of gold in this system. To test the effect of AuTM on PR-mediated transcription, we transfected the progestin-inducible expression vector pMSG-CAT into T-47D cells. Transfected cells were incubated in the absence or presence of AuTM and treated with the synthetic progestin ORG2058, to induce chloramphenicol acetyl transferase (CAT) activity. With 10 and 100 microM AuTM, there was inhibition to 67 +/- 3% (p = 0.012) and 42 +/- 8% (p = 0.008) of CAT specific activity, respectively, compared with controls. These results demonstrate that AuTM can regulate gene expression and that inhibition of binding of a transcription factor to its response element is a likely mechanism. This provides a molecular model for further study of the antirheumatic action of gold salts.
Mol Pharmacol 1991 Nov
PMID:Inhibition of DNA binding and transcriptional activity of a nuclear receptor transcription factor by aurothiomalate and other metal ions. 194 34

We describe the cloning of four novel members of the steroid hormone receptor superfamily of ligand-activated transcription factors. Using chimaeric receptors we demonstrate that one of the receptor homologues is activated by the diverse peroxisome proliferator class of rodent hepatocarcinogens that includes hypolipidaemic drugs and industrial plasticisers. The identification of this receptor homologue should help elucidate the hypolipidaemic mechanism of these compounds and aid our evaluation of their potential carcinogenic risk to man.
J Steroid Biochem Mol Biol 1991
PMID:Cloning of novel members of the steroid hormone receptor superfamily. 195 30

An increasing body of evidence suggests that breast tumour growth is mediated by oncogene products and growth factors which are or which act through cell surface receptors. The aims of the present study were to determine how three of these receptors, c-erbB-2 protein, epidermal growth factor receptor (EGFr) and the beta-subunit of platelet-derived growth factor receptor (PDGFr-beta-subunit), can effectively be demonstrated by immunohistochemical methods in breast tumors, how these receptors are distributed at the cellular level and how their expression correlates with well-established prognostic indicators including hormone receptors and proliferative index. We examined frozen tissue sections of 50 invasive human breast carcinomas, including 45 ductal, four lobular, and one mucinous tumours, by immunocytochemical methods to determine the in situ distributions of c-erbB-2, EGFr, and PDGFr-beta-subunit. We compared staining for c-erbB-2 protein in frozen sections with that in paraffin sections of the same 50 tumours. The immunohistochemical labelling results were compared with tissue hormone receptor content and growth fraction determined by Ki-67 labelling. Strong labelling of tumour cells in frozen sections was detected in 22% of cases, all of the ductal type, stained with rabbit antiserum to c-erbB-2. Labelling for c-erbB-2 protein was generally weaker in paraffin sections than in frozen sections and in six of 11 positive cases, specific staining could be detected only in frozen sections. In immunostains with monoclonal antibody to EGFr, rare cells within tumour were labelled in 60% of the carcinomas. Using a monoclonal antibody to the beta-subunit of PDGFr, consistent labelling of fibrillary cellular processes in the walls of blood vessels and in fibrous stroma around tumour cell nests was detected, but there was no labelling of tumour cells themselves. C-erbB-2 oncoprotein positive tumours were found to be more often oestrogen receptor negative (P less than 0.005) or oestrogen and progesterone receptor negative (P less than 0.01) than c-erbB-2 negative tumours. No significant correlation was observed between c-erbB-2 expression and Ki-67 growth fraction.
Mol Cell Probes 1990 Feb
PMID:In situ distribution of oncogene products and growth factor receptors in breast carcinoma: c-erbB-2 oncoprotein, EGFr, and PDGFr-beta-subunit. 196 11

The mating-type genes at MAT in Saccharomyces cerevisiae are expressed, whereas the same genes located at HML and HMR are transcriptionally repressed. The DNA element responsible for repression at HMR has been termed a silencer and contains an autonomous replication sequence, a binding site for GRFI/RAPI, and a binding site for ABFI. A double-mutant HMR-E silencer that contains single nucleotide substitutions in both the GRFI/RAPI- and ABFI-binding sites no longer binds either factor in vitro, nor represses transcription at HMR in vivo. In MAT alpha cells, this derepression of a information results in a nonmating phenotype. Second-site suppressor mutations were isolated that restored the alpha mating phenotype to MAT alpha cells containing the double-mutant silencer. One of these suppressors, designated sas1-1, conferred a temperature-sensitive lethal phenotype to the cell. SAS1 was found to be identical to CDC7, a gene which encodes a protein kinase required for the initiation of DNA replication. This new allele of CDC7 was designated cdc7-90. cdc7-90 restored the alpha mating phenotype by restoring silencing. The original allele of CDC7, isolated on the basis of the cell cycle phenotype it confers, also restored silencing, and overexpression of CDC7 interfered with silencing. cdc7-90 did not restore detectable binding of GRFI/RAPI or ABFI to the double-mutant silencer in vitro. These results indicate that a reduced level of CDC7 function restores silencing to a locus defective in binding two factors normally required for silencing.
Mol Cell Biol 1991 Feb
PMID:A role for CDC7 in repression of transcription at the silent mating-type locus HMR in Saccharomyces cerevisiae. 199 Feb 68

The role of growth factor signal transducers in the induction of the progesterone receptor by epidermal growth factor (EGF) and the potential sites of EGF antagonism by an antiestrogen were studied in fetal uterine cells in culture. The effects of EGF and estradiol were not additive, suggesting that EGF and estradiol are acting through common mechanisms where antiestrogens could possibly intervene. Fetal uterine cells in culture were found to contain specific, high affinity binding sites for [125I]EGF. Estradiol treatment of the cells led to a higher number of binding sites, but the site of action of 4-hydroxytamoxifen is not the EGF receptor because this antiestrogen had no effect on EGF binding. Activation of protein kinase C by a phorbol ester (12-O-tetradecanoylphorbol 13-acetate) increased progesterone receptor levels to a similar extent as EGF or estradiol. Increasing the intracellular cAMP concentrations by either adding dibutyryl cyclic AMP or activating adenylate cyclase with forskolin also raised progesterone receptor concentrations. Neither the phorbol ester nor dibutyryl cAMP had any effect on cell proliferation. 4-Hydroxytamoxifen completely abolished the effects of the phorbol ester and cAMP. In conclusion, the levels of an estrogen-induced steroid hormone receptor can be regulated by molecules involved in the signal transduction pathway of peptide factors. Moreover, in fetal uterine cells, a potent antiestrogen appears to act as a multiple antagonist but only on an estrogen-inducible response.
Mol Cell Endocrinol 1990 Mar 05
PMID:Stimulation of progesterone receptors by phorbol ester and cyclic AMP in fetal uterine cells in culture. 215 66

Endogenous mouse mammary tumor virus (MMTV) proviral transcripts are up regulated during the normal course of B-lymphocyte differentiation. We report here that the regulatory mechanisms which lead to increased levels of MMTV transcripts in differentiating, lipopolysaccharide (LPS)-stimulated normal B cells and in the inducible B-cell lymphoma line CH12 are at least partially distinct from those controlling increases in immunoglobulin and J-chain gene expression. In studies designed to characterize the stimulatory pathways leading to MMTV expression in CH12 cells, we found that stimulation with either LPS or dexamethasone (Dex), a transcriptional activator of MMTV genes, induced not only MMTV expression but also differentiation to antibody secretion. Only Dex-induced and not LPS-induced MMTV expression and differentiation were inhibited by the glucocorticoid antagonist RU486, demonstrating that Dex and LPS stimulate B cells by distinct molecular pathways. Therefore, in B cells, MMTV expression can be regulated via either the conventional hormone receptor-dependent pathway or a hormone receptor-independent pathway. Furthermore, these results suggest that steroid stimulation of B cells can lead to alterations in the expression of other results suggest that steroid stimulation of B cells can lead to alterations in the expression of other steroid-responsive genes that can become involved in the process of B-cell differentiation.
Mol Cell Biol 1990 Aug
PMID:Lipopolysaccharide and dexamethasone induce mouse mammary tumor proviral gene expression and differentiation in B lymphocytes through distinct regulatory pathways. 216 35

Using biochemical methods we established that estrogen receptor content and distribution and progesterone receptor content in female and male baboon myocardium did not differ between sexes. In contrast, myocardial androgen receptor distribution between cytosolic and nuclear compartments was sexually dimorphic. Female baboon myocardial androgen receptors were restricted to the cytosolic compartment, whereas male myocardial androgen receptors were distributed between the cytosolic and nuclear compartments. Using human estrogen receptor cDNA we showed that baboon aorta, myocardium and uterus contain a 6.3 kb estrogen receptor transcript. Analyses performed with human progesterone receptor cDNA established that baboon aorta and uterus contain an 8 kb progesterone receptor transcript; however, progesterone receptor transcripts were not demonstrable in baboon myocardial RNA preparations. Because relative hybridization signal intensity reflected known uterine and aortic progesterone receptor content, failure to detect progesterone receptor transcripts in myocardial preparations may reflect sensitivity limitations and the fact that aortic progesterone receptor content is 5-fold greater than that of myocardium. Immunocytochemical analyses demonstrated that baboon myocardial progesterone receptors were present in greater than 25% of myocytes and generally absent from other myocardial cells. Our studies establish that: (1) gonadal steroid hormone receptor gene transcription occurs in cells of the baboon cardiovasculature, (2) these steroid hormone receptors may be physiologically functional, and (3) gonadal steroid hormone receptors may be restricted to specialized cells of the cardiovasculature.
J Steroid Biochem Mol Biol 1990 Sep
PMID:Sexual dimorphism characterizes baboon myocardial androgen receptors but not myocardial estrogen and progesterone receptors. 224 55


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