Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endostyle is a pharyngeal organ of uro- chordates, cephalochordates, and primitive vertebrates. This organ has iodine-concentrating and iodine-metabolism activities, and therefore the endostyle is considered to be homologous to the follicle of the thyroid gland. In higher vertebrates the genes for both thyroid transcription factor-1 (TTF-1) and thyroid peroxidase (TPO) are expressed in the thyroid gland follicle. TTF-1 regulates the expression of TPO, which encodes an iodinating enzyme associated with thyroid hormone synthesis. A recent study showed that the ascidian TTF-1 and TPO genes are specifically expressed in the endostyle, but that the expression domains of these genes are not overlapping, suggesting that ascidian TPO is not regulated by TTF-1. To investigate the molecular mechanisms involved in the formation and function of the endostyle, with special reference to the evolution of the follicle of the thyroid gland, I isolated and characterized cDNA clones for the amphioxus homologs of the TTF-1 gene (BbTTF-1) and TPO gene (BbTPO) from Branchiostoma belcheri. Reverse transcriptase-polymerase chain reaction/Southern blotting revealed that both amphioxus TTF-1 and TPO genes are expressed mainly in the adult endostyle. Spatial and temporal expression patterns assessed by in situ hybridization revealed that BbTTF-1 is expressed in the endodermal cells during early embryogenesis and is maintained in all zones of the adult endostyle. On the other hand, expression of BbTPO is chiefly in zones 5 and 6 of the adult endostyle where it overlaps with that of BbTTF-1, and to a lesser extent in zones 1 and 3. This restriction of the expression of BbTTF-1 and BbTPO to the endostyle strongly suggests that the endostyle is homologous to the follicle of the thyroid gland. Moreover, the spatial and temporal expression patterns of these genes suggest that TTF-1 regulates TPO expression. The coexpression of these genes in amphioxus suggests that regulation of TPO by TTF-1 was present in the common ancestor of cephalochordates (acraniates) and craniates.
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PMID:Overlapping expression of amphioxus homologs of the thyroid transcription factor-1 gene and thyroid peroxidase gene in the endostyle: insight into evolution of the thyroid gland. 1118 Aug 27

Studies were carried out to elucidate the mechanism whereby thyroid hormone (T3) induces NADPH:cytochrome P450 oxidoreductase (P450R) mRNA in rat liver in vivo. Northern blot analysis revealed that T3 treatment increases unspliced liver nuclear P450R RNA 4-fold within 8 h and that this induction precedes the induction of mature, cytoplasmic P450R RNA. Unspliced nuclear P450R RNA was suppressed below basal levels 24 h after T3 treatment, despite the continued presence of elevated circulating T3 levels. To determine whether the T3-stimulated increase in nuclear P450R RNA reflects an increase in P450R transcription initiation, nuclear run-on transcription assays were carried out. T3 induced a 6- to 8-fold increase in P450R transcription rate within 12 h, sufficient to account for the observed increase in nuclear P450R precursor RNA, followed by a decrease back to basal transcription levels at 24 h, consistent with the nuclear RNA profile. Similar transcriptional increases were observed in nuclear run-on transcription studies using hybridization probes corresponding to nine different fragments of the P450R gene, spanning exon 2 to exon 16. Thus, P450R transcription initiation, not transcription elongation, is the T3-regulated event. Similar results were obtained during short (5 min) compared with long (45 min) nuclear run-on transcription assays, suggesting that changes in nuclear RNA processing or regulated degradation do not contribute to the overall RNA induction. This finding was confirmed by the ability of the RNA polymerase inhibitor actinomycin D, administered in vivo, to block T3 induction of P450R transcriptional activity. We conclude that P450R transcription, rather than nuclear RNA processing or mRNA stabilization, is the primary mechanism whereby T3 induces hepatic P450R mRNA.
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PMID:Transcriptional induction of hepatic NADPH: cytochrome P450 oxidoreductase by thyroid hormone. 1130 80

Nuclear hormone receptors are ligand-activated transcription factors that regulate the expression of genes that are essential for development, reproduction and homeostasis. The hormone response is mediated through recruitment of p160 receptor coactivators and the general transcriptional coactivator CBP/p300, which function synergistically to activate transcription. These coactivators exhibit intrinsic histone acetyltransferase activity, function in the remodelling of chromatin, and facilitate the recruitment of RNA polymerase II and the basal transcription machinery. The activities of the p160 coactivators are dependent on CBP. Both coactivators are essential for proper cell-cycle control, differentiation and apoptosis, and are implicated in cancer and other diseases. To elucidate the molecular basis of assembling the multiprotein activation complex, we undertook a structural and thermodynamic analysis of the interaction domains of CBP and the activator for thyroid hormone and retinoid receptors. Here we show that although the isolated domains are intrinsically disordered, they combine with high affinity to form a cooperatively folded helical heterodimer. Our study uncovers a unique mechanism, called 'synergistic folding', through which p160 coactivators recruit CBP/p300 to allow transmission of the hormonal signal to the transcriptional machinery.
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PMID:Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. 1182 64

The cellular retinoic acid binding protein I gene is induced by thyroid hormone (T3) through a T3 response element (TRE) approximately 1 kb upstream of the basal promoter. The upstream region is organized into a positioned nucleosomal array with the N1 nucleosome spanning the GC box region. T3 induces apparent interactions between chromatin segments containing the TRE and the GC box regions and the sliding of upstream nucleosomes toward N1 with concomitant N1 remodeling. Concurrently, the chromatin-remodeling factor BRM is replaced by BRG1 and histones are hyperacetylated. All these events are abolished in Med1/Trap220 null cells, indicating a key role for TRAP/Mediator in these processes. A MED1/TRAP220-containing Mediator complex constitutively occupies the GC box region but not the TRE, serving as a nexus for distal and proximal factors. This indicates new TRAP/Mediator functions in facilitating ultimate recruitment and function of RNA polymerase II and the general transcription machinery.
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PMID:Thyroid hormone-induced juxtaposition of regulatory elements/factors and chromatin remodeling of Crabp1 dependent on MED1/TRAP220. 1613 21

Thyroid hormone receptors (TRs) are ligand-regulated transcription factors that bind to thyroid hormone response elements of target genes. Upon ligand binding, they recruit coactivator complexes that increase histone acetylation and recruit RNA polymerase II (Pol II) to activate transcription. Recent studies suggest that nuclear receptors and coactivators may have temporal recruitment patterns on hormone response elements, yet little is known about the nature of the patterns at multiple endogenous target genes. We thus performed chromatin immunoprecipitation assays to investigate coactivator recruitment and histone acetylation patterns on the thyroid hormone response elements of four endogenous target genes (GH, sarcoplasmic endoplasmic reticulum calcium-adenosine triphosphatase, phosphoenolpyruvate carboxykinase, and cholesterol 7alpha-hydroxylase) in a rat pituitary cell line that expresses TRs. We found that TRbeta, several associated coactivators (steroid receptor coactivator-1, glucocorticoid receptor interacting protein-1, and TR-associated protein 220), and RNA Pol II were rapidly recruited to thyroid hormone response elements as early as 15 min after T3 addition. When the four target genes were compared, we observed differences in the types and temporal patterns of recruited coactivators and histone acetylation. Interestingly, the temporal pattern of RNA Pol II was similar for three genes studied. Our findings suggest that thyroid hormone-regulated target genes may have distinct patterns of coactivator recruitment and histone acetylation that may enable highly specific regulation.
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PMID:Thyroid hormone-regulated target genes have distinct patterns of coactivator recruitment and histone acetylation. 1625 15

The TRAP/Mediator coactivator complex serves as a functional interface between DNA-bound transactivators and the RNA polymerase II-associated basal transcription apparatus. TRAP220/MED1 is a variably associated subunit of the complex that plays a specialized role in selectively targeting TRAP/Mediator to specific genes. Ablation of the Trap220/Med1 gene in mice impairs embryonic cell growth, yet the underlying mechanism is unknown. In this report, we identified distinct cell growth regulatory genes whose expression is affected by the loss of TRAP220/MED1 by RNA interference. Among the down-regulated genes revealed by cDNA microarray analyses, we identified Aurora-A, a centrosome kinase that plays a critical role in regulating M phase events and is frequently amplified in several types of cancer. In general, we found that TRAP220/MED1 expression is required for high basal levels of Aurora-A gene expression and that ectopic overexpression of TRAP220/MED1 coactivates transcription from the Aurora-A gene promoter. Furthermore, chromatin immunoprecipitation assays show that TRAP220/MED1-containing TRAP/Mediator complexes directly bind to the Aurora-A promoter in vivo. Finally, we present evidence suggesting that TRAP/Mediator is recruited to the Aurora-A gene via direct interactions between TRAP220/MED1 and the Ets-related transcription factor GABP. Taken together, these findings suggest that TRAP220/MED1 plays a novel coregulatory role in facilitating the recruitment of TRAP/Mediator to specific target genes involved in growth and cell cycle progression.
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PMID:Regulation of Aurora-A kinase gene expression via GABP recruitment of TRAP220/MED1. 1657 58

IL-8 is a chemokine that recruits migrating neutrophils and leukocytes to areas of inflammation. In noninflamed tissue, IL-8 expression is low but can be rapidly induced by proinflammatory cytokines. Typically, inflammation and transient IL-8 expression are beneficial. However, some diseases are characterized by excessive inflammation and high levels of IL-8. Previous studies have shown that IFN-beta can inhibit the expression of IL-8, although the mechanism is unknown. Using chromatin immunoprecipitation assays, we define the IL-8 transcriptional program in the absence or presence of inducing stimuli and/or inhibition by IFN-beta. In the absence of stimuli, the IL-8 promoter is acetylated but negatively regulated by corepressor proteins. Upon PMA stimulation, the levels of these corepressors are reduced and the promoter is rapidly bound and activated by transcription factors, including NF-kappaB p65, C/EBPbeta, and c-Fos. In addition, RNA polymerase II is recruited to the IL-8 promoter to initiate transcription. However, in the presence of both PMA and IFN-beta, there are diminished levels of histone acetylation, reduced levels of transcription factors such as NF-kappaB p65 and RNA polymerase II, and an increased presence of corepressor proteins such as histone deacetylases 1 and 3 and silencing mediator of retinoic acid and thyroid hormone receptors. IFN-gamma-inducible protein-10 and MCP-1 genes, also regulated by NF-kappaB, are unaffected by IFN-beta, and IFN-beta does not prevent the activation, nuclear migration, or binding of NF-kappaB p65 to the kappaB element of the IFN-gamma-inducible protein-10 promoter. As such, these data show that the inhibitory effects of IFN-beta are specific to the IL-8 promoter.
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PMID:Mechanism of IFN-beta-mediated inhibition of IL-8 gene expression in astroglioma cells. 1681 36

ING (INhibitor of Growth) tumor suppressor proteins are epigenetic factors involved in numerous cellular processes including apoptosis in species ranging from yeast to humans. We recently isolated ING1 and ING2 transcript variants in Xenopus laevis and showed that these transcripts were differentially regulated by thyroid hormone (TH) during postembryonic development. However, no information exists regarding ING gene structure and how it relates to these differential responses to TH. To further investigate the regulation of ING genes by TH, we isolated ING1 and ING2 gene sequences and demonstrated that there are at least duplicate genes for each. The relationship between transcript variants and their responsiveness to TH were examined through promoter sequence and chromatin immunoprecipitation analyses on tail homogenates. Both TH receptors (TRs) differentially associated with ING1 and ING2 promoter regions with increased recruitment in the presence of TH. This occurred irrespective of gene transcript level response to this hormone. However, differential recruitment of RNA polymerase II corresponded well to transcript levels. ING proteins consistently associated with their own gene promoters except in the region generating the TH-inducible xING1b5 transcript. In this case, a substantial recruitment of TRbeta in the absence ING proteins occurred. These data establish the TH-dependent recruitment of transcription factors to ING promoter regions and suggest that differential TR recruitment in response to TH may not be a sufficient indicator for modulating the expression of ING in the tail.
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PMID:Multiple ING1 and ING2 genes in Xenopus laevis and evidence for differential association of thyroid hormone receptors and ING proteins to their promoters. 1816 18

Dysfunction in thyroid regulation can cause menstrual and ovulatory disturbances, the mechanism of which is not clear. The distribution and activity of the thyroid-stimulating hormone (TSHR), and the thyroid hormone receptors (TR) alpha1, alpha2 and beta1 in human ovarian tissue and in granulosa cells was studied using immunohistochemistry, reverse-transcriptase polymerase chain reaction (RT-PCR), quantitative PCR and immunoassays. Strong immunostaining of TSHR, TRalpha1 and TRbeta1 was observed in ovarian surface epithelium and in oocytes of primordial, primary and secondary follicles, with minimal staining in granulosa cells of secondary follicles. Granulosa cells of antral follicles expressed TSHR, TRalpha1 and TRbeta1 proteins. Messenger RNA for all receptors was present in ovarian tissue. Mature human granulosa cells expressed transcripts for 5' deiodinases types 2 and 3, but not type 1, indicating the possibility of conversion of peripheral thyroid hormone thyroxin (T(4)). Granulosa cells stimulated with TSH showed a significant increase in cAMP concentrations after 2 h of culture (P = 0.047), indicating activation through TSHR. Stimulation with T(4) resulted in increased extracellular signal-regulated kinase 1 and 2 activation after 10, 30, 60 min and 24 h. These data demonstrate that TSH and thyroid hormone receptors may participate in the regulation of ovarian function.
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PMID:Receptors for thyroid-stimulating hormone and thyroid hormones in human ovarian tissue. 1929 32

We reported a novel mutation of thyroid hormone receptor (TR)-beta, F455S, in a patient with pituitary resistance to thyroid hormone (RTH), who showed impaired release of nuclear receptor corepressor and abnormal histone deacetylation. In the present study, we further analyzed the histone modifications and the dynamics of TR and RNA polymerase II on the TRH gene. The lysine residues 9 (H3K9) and 14 (K14) of the histone H3 were acetylated in the absence of thyroid hormone (TH), and addition of TH caused a temporary deacetylation of both residues. Although H3K4 was di- and trimethylated in the absence of T(3), no methylation of H3K9 or K27 was detected. Long-term incubation with T(3) decreased the level of trimethylated H3K4, the amount of TR, and the level of phosphorylated RNA polymerase II but not dimethylated H3K4. Treatment with an inhibitor for H3K4 methyltransferase, 5'-deoxy-5'-methylthioadenosine, decreased basal promoter activity but did not affect the repression by TH. Conversely, overexpression of MLL, an H3K4-specific methyltransferase, caused an increase in basal activity. In the presence of F455S, methylation of H3K4 and the dynamics of TR were intact, but both H3K9 and H3K14 were hyperacetylated, and T(3)-induced deacetylation was impaired, resulting in a high transcriptional level. These findings demonstrated that 1) negative regulation of the TRH gene by TH involves both the acetylation and methylation of specific residues of histone tails and changing the amount of TR, and 2) the major impairment to histone modifications in F455S was hyperacetylation of the specific histone tails.
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PMID:Aberrant histone modifications at the thyrotropin-releasing hormone gene in resistance to thyroid hormone: analysis of F455S mutant thyroid hormone receptor. 1929 58


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