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)

Clearance and adaptation to reactive oxygen species (ROS) are crucial for cell survival. As in other eukaryotes, the Neurospora catalases are the main enzymes responsible for ROS clearance and their expression are tightly regulated by the growth and environmental conditions. The RNA polymerase II carboxyl terminal domain (RNAPII CTD) kinase complex (CTK complex) is known as a positive elongation factor for many inducible genes by releasing paused RNAPII near the transcription start site and promoting transcription elongation. However, here we show that deletion of CTK complex components in Neurospora led to high CAT-3 expression level and resistance to H₂ O₂ -induced ROS stress. The catalytic activity of CTK-1 is required for such a response. On the other hand, CTK-1 overexpression led to decreased expression of CAT-3. ChIP assays shows that CTK-1 phosphorylates the RNAPII CTD at Ser2 residues in the cat-3 ORF region during transcription elongation and deletion of CTK-1 led to dramatic decreases of SET-2 recruitment and H3K36me3 modification. As a result, histones at the cat-3 locus become hyperacetylated to promote its transcription. Together, these results demonstrate that the CTK complex is negative regulator of cat-3 expression by affecting its chromatin structure.
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PMID:The Neurospora RNA polymerase II kinase CTK negatively regulates catalase expression in a chromatin context-dependent manner. 3159 77

Various circular RNAs (circRNAs) have been reported to involve in carcinoma. This study explored the role and mechanism of circRNA circFNDC3B (circFNDC3B) in renal carcinoma (RC). The detection indicators in this paper were viability, colony, and migration, which respectively investigated by Cell Counting Kit-8, colony formation, and migration assay. Reverse transcriptase quantitative polymerase chain reaction tested and cell transfection changed circFNDC3B and miR-99a expression. Moreover, western blot tested relate-proteins of proliferation, migration, and cell pathways were examined by western blot. circFNDC3B was upregulated at RC tissues. circFNDC3B enhanced cell viability, colony and migration, and miR-99a mimic played reverse impacts. Furthermore, circFNDC3B negatively regulated miR-99aand circFNDC3B restrained the janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathways by miR-99a downregulation. Overexpression of circFNDC3B enhanced cell viability, colony formation and migration by miR-99a downregulation via JAK1/STAT3 and MEK/ERK pathways.
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PMID:Circular RNA circFNDC3B protects renal carcinoma by miR-99a downregulation. 3163 4

Differentially methylated genes (DMGs) serve a crucial role in the pathogenesis of glioma via the regulation of the cell cycle, proliferation, apoptosis, migration, infiltration, DNA repair and signaling pathways. This study aimed to identify aberrant DMGs and pathways by comprehensive bioinformatics analysis. The gene expression profile of GSE28094 was downloaded from the Gene Expression Omnibus (GEO) database, and the GEO2R online tool was used to find DMGs. Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the DMGs were performed by using the Database for Annotation Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was constructed with Search Tool for the Retrieval of Interacting Genes. Analysis of modules in the PPI networks was performed by Molecular Complex Detection in Cytoscape software, and four modules were performed. The hub genes with a high degree of connectivity were verified by The Cancer Genome Atlas database. A total of 349 DMGs, including 167 hypermethylation genes, were enriched in biological processes of negative and positive regulation of cell proliferation and positive regulation of transcription from RNA polymerase II promoter. Pathway analysis enrichment revealed that cancer regulated the pluripotency of stem cells and the PI3K-AKT signaling pathway, whereas 182 hypomethylated genes were enriched in biological processes of immune response, cellular response to lipopolysaccharide and peptidyl-tyrosine phosphorylation. Pathway enrichment analysis revealed cytokine-cytokine receptor interaction, type I diabetes mellitus and TNF signaling pathway. A total of 20 hub genes were identified, of which eight genes were associated with survival, including notch receptor 1 (NOTCH1), SRC proto-oncogene (also known as non-receptor tyrosine kinase, SRC), interleukin 6 (IL6), matrix metallopeptidase 9 (MMP9), interleukin 10 (IL10), caspase 3 (CASP3), erb-b2 receptor tyrosine kinase 2 (ERBB2) and epidermal growth factor (EGF). Therefore, bioinformatics analysis identified a series of core DMGs and pathways in glioma. The results of the present study may facilitate the assessment of the tumorigenicity and progression of glioma. Furthermore, the significant DMGs may provide potential methylation-based biomarkers for the precise diagnosis and targeted treatment of glioma.
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PMID:Identification of core differentially methylated genes in glioma. 3178 78

Human noroviruses (HuNoV) are a leading cause of viral gastroenteritis worldwide and a significant cause of morbidity and mortality in all age groups. The recent finding that HuNoV can be propagated in B cells and mucosa-derived intestinal epithelial organoids (IEOs) has transformed our ability to dissect the life cycle of noroviruses. Using transcriptome sequencing (RNA-Seq) of HuNoV-infected intestinal epithelial cells (IECs), we have found that replication of HuNoV in IECs results in interferon (IFN)-induced transcriptional responses and that HuNoV replication in IECs is sensitive to IFN. This contrasts with previous studies that suggested that the innate immune response may play no role in the restriction of HuNoV replication in immortalized cells. We demonstrated that inhibition of Janus kinase 1 (JAK1)/JAK2 enhanced HuNoV replication in IECs. Surprisingly, targeted inhibition of cellular RNA polymerase II-mediated transcription was not detrimental to HuNoV replication but instead enhanced replication to a greater degree than blocking of JAK signaling directly. Furthermore, we demonstrated for the first time that IECs generated from genetically modified intestinal organoids, engineered to be deficient in the interferon response, were more permissive to HuNoV infection. Taking the results together, our work revealed that IFN-induced transcriptional responses restrict HuNoV replication in IECs and demonstrated that inhibition of these responses mediated by modifications of the culture conditions can greatly enhance the robustness of the norovirus culture system.IMPORTANCE Noroviruses are a major cause of gastroenteritis worldwide, and yet the challenges associated with their growth in culture have greatly hampered the development of therapeutic approaches and have limited our understanding of the cellular pathways that control infection. Here, we show that human intestinal epithelial cells, which represent the first point of entry of human noroviruses into the host, limit virus replication by induction of innate responses. Furthermore, we show that modulating the ability of intestinal epithelial cells to induce transcriptional responses to HuNoV infection can significantly enhance human norovirus replication in culture. Collectively, our findings provide new insights into the biological pathways that control norovirus infection but also identify mechanisms that enhance the robustness of norovirus culture.
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PMID:Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses. 3218 38

To elucidate dynamic changes in native BCR-ABL and alternatively spliced tyrosine kinase inhibitor (TKI)-resistant but function-dead BCR-ABL^Ins35bp variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR-ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR-ABL^Ins35bp , accounting for 0.8% of the total IS BCR-ABL, corresponding to actual BCR-ABL^Ins35bp value of 1.1539% IS. TKI rapidly decreased native BCR-ABL but not BCR-ABL^Ins35bp , leading to the initial increase in the proportion of BCR-ABL^Ins35bp . Thereafter, both native BCR-ABL and BCR-ABL^Ins35bp gradually decreased in the course of TKI treatment, whereas small populations positive for TKI-resistant BCR-ABL^Ins35bp continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR-ABL⁺ clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function-dead BCR-ABL^Ins35bp , suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis-splicing BCR-ABL^Ins35bp , occurring at the particular pseudo-splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR-ABL extracting BCR-ABL^Ins35bp would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.
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PMID:Tyrosine kinase inhibitors induce alternative spliced BCR-ABL^Ins35bp variant via inhibition of RNA polymerase II on genomic BCR-ABL. 3231 54

The positive transcription elongation factor b (P-TEFb), composed of CDK9 and cyclin T, stimulates transcriptional elongation by RNA polymerase (Pol) II and regulates cell growth and differentiation. Recently, we demonstrated that P-TEFb also controls the expression of EMT regulators to promote breast cancer progression. In the nucleus, more than half of P-TEFb are sequestered in the inactive-state 7SK snRNP complex. Here, we show that the assembly of the 7SK snRNP is preceded by an intermediate complex between HEXIM1 and P-TEFb that allows transfer of the kinase active P-TEFb from Hsp90 to 7SK snRNP for its suppression. Down-regulation of HEXIM1 locks P-TEFb in the Hsp90 complex, keeping it in the active state to enhance breast cancer progression, but also rendering the cells highly sensitive to Hsp90 inhibition. Because HEXIM1 is often down-regulated in human triple-negative breast cancer (TNBC), these cells are particularly sensitive to Hsp90 inhibition. Our study provides a mechanistic explanation for the increased sensitivity of TNBC to Hsp90 inhibition.
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PMID:HEXIM1 controls P-TEFb processing and regulates drug sensitivity in triple-negative breast cancer. 3252 Jun 33

BACKGROUND The underlying mechanism of insulin resistance is complex; bioinformatics analysis is used to explore the mechanism based differential expression genes (DEGs) obtained from omics analysis. However, the expression and role of most DEGs involved in bioinformatics analysis are invalidated. This study aimed to disclose the mechanism of insulin resistance via bioinformatics analysis based on validated insulin resistance-related genes (IRRGs) collected from public disease-gene databases. MATERIAL AND METHODS IRRGs were collected from 4 disease databases including NCBI-Gene, CTD, RGD, and Phenopedia. GO and KEGG analysis of IRRGs were performed by DAVID. Then, the STRING database was employed to construct a protein-protein interaction (PPI) network of IRRGs. The module analysis and hub genes identification were carried out by MCODE and cytoHubba plugin of Cytoscape based on the primary PPI network, respectively. RESULTS A total of 1195 IRRGs were identified. Response to drug, hypoxia, insulin, positive regulation of transcription from RNA polymerase II promoter, cell proliferation, inflammatory response, negative regulation of apoptotic process, glucose homeostasis, cellular response to insulin stimulus, and aging were proposed as the crucial functions related to insulin resistance. Ten insulin resistance-related pathways included the pathways of insulin resistance, pathways in cancer, adipocytokine, prostate cancer, PI3K-Akt, insulin, AMPK, HIF-1, prolactin, and pancreatic cancer signaling pathway were revealed. INS, AKT1, IL-6, TP53, TNF, VEGFA, MAPK3, EGFR, EGF, and SRC were identified as the top 10 hub genes. CONCLUSIONS The current study presented a landscape view of possible underlying mechanism of insulin resistance by bioinformatics analysis based on validated IRRGs.
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PMID:Underlying Mechanism of Insulin Resistance: A Bioinformatics Analysis Based on Validated Related-Genes from Public Disease Databases. 3265 53

Colorectal cancer (CRC) is the most common malignant gastrointestinal tumor worldwide. Serum exosomal microRNAs (miRNAs) play a critical role in tumor progression and metastasis. However, the underlying molecular mechanisms are poorly understood.The miRNAs expression profile (GSE39833) was downloaded from Gene Expression Omnibus (GEO) database. GEO2R was applied to screen the differentially expressed miRNAs (DEmiRNAs) between healthy and CRC serum exosome samples. The target genes of DEmiRNAs were predicted by starBase v3.0 online tool. The gene ontology (GO) and Kyoto Encyclopedia of Genomes pathway (KEGG) enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. The protein-protein interaction (PPI) network was established by the Search Tool for the Retrieval of Interacting Genes (STRING) visualized using Cytoscape software. Molecular Complex Detection (MCODE) and cytohubba plug-in were used to screen hub genes and gene modules.In total, 102 DEmiRNAs were identified including 67 upregulated and 35 downregulated DEmiRNAs, and 1437 target genes were predicted. GO analysis showed target genes of upregulated DEmiRNAs were significantly enriched in transcription regulation, protein binding, and ubiquitin protein ligase activity. While the target genes of downregulated DEmiRNAs were mainly involved in transcription from RNA polymerase II promoter, SMAD binding, and DNA binding. The KEGG pathway enrichment analyses showed target genes of upregulated DEmiRNAs were significantly enriched in proteoglycans in cancer, microRNAs in cancer, and phosphatidylinositol-3 kinases/Akt (PI3K-Akt) signaling pathway, while target genes of downregulated DEmiRNAs were mainly enriched in transforming growth factor-beta (TGF-beta) signaling pathway and proteoglycans in cancer. The genes of the top 3 modules were mainly enriched in ubiquitin mediated proteolysis, spliceosome, and mRNA surveillance pathway. According to the cytohubba plugin, 37 hub genes were selected, and 4 hub genes including phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), SRC, cell division cycle 42 (CDC42), E1A binding protein p300 (EP300) were identified by combining 8 ranked methods of cytohubba.The study provides a comprehensive analysis of exosomal DEmiRNAs and target genes regulatory network in CRC, which can better understand the roles of exosomal miRNAs in the development of CRC. However, these findings require further experimental validation in future studies.
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PMID:Investigating potential molecular mechanisms of serum exosomal miRNAs in colorectal cancer based on bioinformatics analysis. 3292 95


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