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)

Somatostatin (SRIH) analogs can suppress the proliferation of human differentiated thyroid carcinoma cell lines that express SRIH receptors (SSTRs) demonstrated by radioligand binding analysis. Five distinct human SSTR subtypes (hSSTR1-5) that bind native SRIH exhibit diverse affinities to a wide range of SRIH analogs. Reverse transcriptase-PCR amplification of ribonucleic acids (RNAs) obtained from normal thyroid tissues and nine human thyroid carcinoma cell lines, grown as monolayer cultures and xenograft tumors in nude mice, were used to discriminate expression of SSTR subtype messenger RNAs (mRNAs). The cell lines were derived from a follicular adenoma (KAK-1), two follicular carcinomas (MRO-87 and WRO-82), two papillary carcinomas (NPA87 and KAT-10), and four anaplastic thyroid carcinomas (DRO-90, ARO-81, KAT-4, and KAT-18). Most thyroid cancer cell line monolayers and xenografts expressed SSTR3 and SSTR5 mRNAs. SSTR1 expression was more varied between monolayers and xenografts, whereas SSTR2 mRNA was only faintly detectable at the most extreme resolution. SSTR4 mRNA was faintly positive in only one anaplastic carcinoma xenograft. Normal thyroid also expressed SSTR3 and SSTR5 mRNAs, with only faint expression of SSTR1 and SSTR2 mRNAs (in one of five and three of five samples, respectively). SSTR mRNA expression was dependent upon in vitro culture conditions, as xenograft SSTR mRNA expression tended to decrease compared to that in each respective monolayer culture. Characterization of SSTR subtype expression in human thyroid carcinomas may permit targeting of specific SRIH analogs to inhibit proliferation of differentiated and anaplastic thyroid carcinomas in patients.
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PMID:Somatostatin receptor subtype expression in human thyroid and thyroid carcinoma cell lines. 917 96

Reverse transcriptase-PCR has identified thyroglobulin mRNA (Tg mRNA) in peripheral blood of normal adults and adults with thyroid cancer. However, no children were studied. The primary objective of this study was to determine whether whole blood Tg mRNA levels differ between benign and malignant thyroid disease in children. The secondary goals were to determine whether whole blood Tg mRNA levels vary with age or pubertal development among children with thyroid disease. Whole blood Tg mRNA levels were determined in 38 children (29 girls, nine boys; median age, 14.5 y; range, 4.8-20.4 y) with benign and malignant thyroid disease and correlated with diagnosis, age, pubertal status, thyroid size, and serum levels of free thyroxine, TSH, and Tg protein. Tg mRNA levels ranged from 3.3 to 104 pg Eq/microg total thyroid RNA (mean, 28 +/- 20.2 pg Eq/microg total thyroid RNA) and were similar in benign and malignant disorders (p = 0.67). However, in children with previously treated papillary thyroid cancer, Tg mRNA levels directly correlated with total body (131)I uptake (p = 0.026) and serum Tg protein (p = 0.037). There was no difference between boys and girls, and no change with pubertal maturation. In children with benign thyroid disease, Tg mRNA levels correlated with serum TSH (p = 0.031), but not with diagnosis, age, Tanner stage, or thyroid size. We conclude that Tg mRNA levels are similar in children with benign and malignant thyroid disease and unchanged by age or pubertal status, but correlated with tumor burden in previously treated papillary thyroid cancer.
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PMID:Thyroglobulin messenger ribonucleic acid levels in the peripheral blood of children with benign and malignant thyroid disease. 1122 72

Available ribonucleic acid (RNA) amplification methods are extensively tested for reproducibility, but only a few studies additionally deal with potential amplification bias. On targeted arrays, we evaluated three amplification protocols, which are less time consuming than the commonly used T7-RNA polymerase based in vitro transcription protocols and therefore may be more suitable for clinical use: Template-switching polymerase chain reaction (PCR), Ribo-single primer isothermal amplification and a random primer-based PCR. Additionally, a more sensitive labelling method, Dendrimer labelling, was evaluated. All methods were compared to unamplified RNA labelled at reverse transcription. From our results, we conclude that RNA amplification with template-switching PCR is highly reproducible and results in a reliable representation of the starting RNA population. We then assessed whether RNA amplification of clinical breast and thyroid cancer samples with template-switching PCR showed robust performance when altered cycle numbers or partially degraded RNA were used. Template-switching PCR proved to be a very reliable method for global RNA amplification, even when starting from partially degraded RNA down to a RNA Integrity Number of 4.3. In conclusion, template-switching PCR amplification promises to help micro-array expression profiling of limited amounts of human samples on its way to a clinical routine.
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PMID:Comparison of RNA amplification techniques meeting the demands for the expression profiling of clinical cancer samples. 1797 98

Telomerase-reverse-transcriptase (TERT) promoter mutations have been recently described in tumors. In the present large series, TERT mutations were found in 12% of papillary thyroid cancers (PTCs) and in 14% of follicular thyroid cancers (FTCs), and were found to significantly correlate with older age at diagnosis and poorer outcome. Interestingly, the prognostic value of TERT mutations resulted to be significantly stronger than that of BRAF(V600E). Moreover, the outcome was not different among tumors with isolated TERT mutation and those with coexistent mutations (TERT/BRAF in PTCs or TERT/RAS in FTCs). TERT rs2853669 polymorphism was found in 44.4% of tumors. At WB, TERT was significantly more expressed in tumors than in normal samples, being the highest levels of expression recorded in TERT mutated cases. At IHC, in tumors and in metastatic lymph-nodes TERT staining was significantly higher in the cytoplasm than in the nucleus, whereas in normal tissue the degree of staining did not differ in the two cellular compartments. In conclusion, TERT mutations were shown to strongly correlate with a poorer outcome in differentiated thyroid tumors, and neither BRAF nor RAS mutation were found to confer an additional effect in the disease persistence. TERT protein was found to be more expressed in neoplastic than in normal tissues, and to display a different cellular localization, suggesting that it could contribute to thyroid cancer progression by mechanisms taking place in the cytoplasm.
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PMID:Telomerase in differentiated thyroid cancer: promoter mutations, expression and localization. 2544 48

DNA methylation is the best-studied epigenetic mechanism for regulating gene transcription and maintaining genome stability. Current research progress of transcriptional regulation by DNA methylation mostly focuses on promoter region where hypomethylated CpG islands are present transcriptional activity, as hypermethylated CpG islands generally result in gene repression. Recently, the DNA methylation patterns across the gene body (intragenic methylation) have increasingly attracted attention towards their role in transcriptional regulation and efficiency, due to the improvement of numerous genome-wide DNA methylation profiling studies. However, the function and mechanism of gene body methylation is still unclear. In this study, we revealed that the methylation level of METTL7A, a seldom studied gene, was downregulated in thyroid cancer compared to normal thyroid cells in vivo and in vitro. Moreover, we determined the methylation level of one CpG site at the exon of the METTL7A gene body impacted the transcriptional activity. Through generating a mutation of this CpG site (CG to CC) of METTL7A exogenous vector artificially in vitro, we observed higher RNA polymerase II recruitment and a declined enrichment of methyl-CpG binding protein-2 in gene body of METTL7A, in papillary thryoid cancer cells (BCPAP) compared to normal thryoid cells. Finally, we revealed that EZH2, a subunit of polycomb repressor complex 2, dominant in thyroid cancer, might be responsible for regulating gene body methylation of METTL7A. Our study depicted the DNA methylation patterns and the transcriptional regulatory mechanism of the gene body in thyroid cancer. Furthermore, this study provides new insight into potential future avenues, for therapies targeting cancer.
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PMID:DNA methylation of METTL7A gene body regulates its transcriptional level in thyroid cancer. 2841 72

BRAF^V600E mutation is frequently found in human cancers particularly thyroid cancer and melanoma, and is involved in the regulation of gene expression through activating MAPK/Erk signaling. Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing in tumorigenesis. However, molecular mechanism underlying the complex interplay between these two molecular events remains to be explored. In the present study, we conducted chromatin immunoprecipitation combined with next-generation sequencing (ChIP-Seq) and expression microarray analysis in NIH3T3 cells to explore the relationship between H3K27me3 and transcriptional regulation by BRAF^V600E mutation. Our results showed that activated MAPK/Erk signaling by BRAF^V600E mutation was a trigger of this epigenetic processing at many downstream target genes in cancer cell lines and Braf^V600E-induced thyroid cancer of transgenetic mice. By integrating ChIP-Seq and gene expression microarray data, we identified 150 down-regulated loci with increased levels of H3K27me3 in BRAF-mutant cells relative to BRAF wild-type cells. Our data also demonstrated that c-Myc, a downstream key effector of BRAF^V600E signaling, was required for BRAF^V600E-induced changes in H3K27me3 through regulating the components of the polycomb repressive complex 2 (PRC2) genes Ezh2, Suz12 and Jarid2 at both transcriptional levels via direct binding to their regulatory elements and post-transcriptional levels via repressing the miR-26a, miR-200b and miR-155. In addition, BRAF^V600E also caused gene silencing through Erk1/2-induced RNA polymerase II (RNAPII) poising and chromatin architecture. Collectively, our data uncover a previously unknown epigenetic mechanism in the tumorigenesis of BRAF^V600E-driven cancers.
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PMID:c-Myc is Required for BRAF^V600E-Induced Epigenetic Silencing by H3K27me3 in Tumorigenesis. 2863 88

Disconnected interacting protein 2 homolog A (DIP2A) is highly expressed in nervous system and respiratory system of developing embryos. However, genes regulated by Dip2a in developing brain and lung have not been systematically studied. Transcriptome of brain and lung in embryonic 19.5 day (E19.5) were compared between wild type and Dip2a-/- mice. An average of 50 million reads per sample was mapped to the reference sequence. A total of 214 DEGs were detected in brain (82 up and 132 down) and 1900 DEGs in lung (1259 up and 641 down). GO enrichment analysis indicated that DEGs in both Brain and Lung were mainly enriched in biological processes 'DNA-templated transcription and Transcription from RNA polymerase II promoter', 'multicellular organism development', 'cell differentiation' and 'apoptotic process'. In addition, COG classification showed that both were mostly involved in 'Replication, Recombination, and Repair', 'Signal transduction and mechanism', 'Translation, Ribosomal structure and Biogenesis' and 'Transcription'. KEGG enrichment analysis showed that brain was mainly enriched in 'Thyroid cancer' pathway whereas lung in 'Complement and Coagulation Cascades' pathway. Transcription factor (TF) annotation analysis identified Zinc finger domain containing (ZF) proteins were mostly regulated in lung and brain. Interestingly, study identified genes Skor2, Gpr3711, Runx1, Erbb3, Frmd7, Fut10, Sox11, Hapln1, Tfap2c and Plxnb3 from brain that play important roles in neuronal cell maturation, differentiation, and survival; genes Hoxa5, Eya1, Errfi1, Sox11, Shh, Igf1, Ccbe1, Crh, Fgf9, Lama5, Pdgfra, Ptn, Rbp4 and Wnt7a from lung are important in lung development. Expression levels of the candidate genes were validated by qRT-PCR. Genome wide transcriptional analysis using wild type and Dip2a knockout mice in brain and lung at embryonic day 19.5 (E19.5) provided a genetic basis of molecular function of these genes.
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PMID:Transcriptome profiling of mouse brain and lung under Dip2a regulation using RNA-sequencing. 3172 91

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, with no effective treatment available. Identification of new anti-ATC drugs represents an urgent need. In this study, we find that ATC cells are highly sensitive to THZ531, a potent inhibitor of the transcriptional cyclin-dependent kinase (CDK), CDK12. Cell-based assays demonstrate that CDK12 inhibition significantly impedes cell cycle progression, induces apoptotic cell death, and impairs colony formation in ATC cells. THZ531 causes a loss of elongating RNA polymerase II and suppresses gene expression in ATC cells. An integrative analysis of gene expression profiles and super-enhancer landscape, combining with functional assays, leads to the discovery of two new ATC cancer genes, ZC3H4 and NEMP1. Furthermore, CDK12 inhibition enhances the sensitivity of ATC cells to doxorubicin-mediated chemotherapy. Thus, these findings indicate that CDK12 is a potential therapeutic target for ATC treatment and its inhibition may help to overcome the chemoresistance in patients with ATC.
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PMID:Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma. 3161 55

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