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

---

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

Following the introduction of highly active antiretroviral therapy (HAART), metabolic and morphological complications known as HIV associated lipodystrophy syndrome (HALS) have been increasingly common. The approaches to target these complications span from resistance exercise, diet and use of the antidiabetics metformin or glitazones to high dose recombinant human growth hormone therapy or switching antiretroviral regimen. When looking at the effect of switching therapy, focus has been addressed to protease inhibitor (PI) based regimens, as PI was the first component of HAART recognized to be correlated with the disfiguring body-alterations known as HALS. More recently, however, regimens containing nucleoside reverse-transcriptase inhibitors (NRTI) have attracted attention. Reviewing switch studies regarding metabolic parameters and body shape changes, certain trends emerge. Switching from PI, the metabolic complications such as dyslipidaemia and insulin resistance seem to be partly reversible, whereas the morphologic alterations appear to be unchanged. In studies in which NRTI's are switched, dyslipidaemia appears unaffected, but a modest improvement in peripheral lipoatrophy has been reported. However the results are often inconsistent and difficult to interpret, mostly because of limitations in study design, patient number and duration of follow-up. The need for larger, controlled, randomized, long-term studies is evident.
...
PMID:Impact of switching antiretroviral therapy on lipodystrophy and other metabolic complications: a review. 1519 79

We sought an in vitro primate model for serotonin neurons. Rhesus monkey embryonic stem (ES) cell colonies were isolated and differentiated into embryoid bodies (EBs), then transferred to serum-free medium with 1% insulin-transferrin-selenium for 7 days to induce neural precursor cell (NPC) formation. NPCs were cultured in medium with 1% N-2 neural supplement and human fibroblast growth factor 2 (FGF2, 10 ng/ml) for 7 days to stimulate cell proliferation. Lastly, NPCs were dispersed into single cells and cultured without FGF2 for another 7 days to obtain terminal differentiation. Terminal cells were characterized for neuronal and serotonergic markers. Over 95% of the NPCs were immunopositive for nestin and Musashi1. Terminally differentiated cells appeared in both small and large morphologies. Most (>95%) of the mature cells (both small and large) were immunopositive for neuron-specific nuclear protein (NeuN), synaptophysin, microtubule-associated protein (MAP2C), Tau-1, neurofilament 160 (NF-160), beta-tubulin (TujIII), tryptophan hydroxylase (TPH), serotonin, the serotonin reuptake transporter (SERT), estrogen receptor-beta (ERbeta), and progestin receptor (PR), but not estrogen receptor-alpha (ERalpha). Less than 2-3% of cells were positive for tyrosine hydroxylase (TH). Reverse transcriptase polymerase chain reaction (RT-PCR) detected mRNA transcripts for TPH-1, TPH-2, SERT, 5-HT1A-autoreceptor, ERbeta, and PR in the differentiated population. A low level of expression of ERalpha mRNA was also detected. Quantitative RT-PCR indicated that the relative abundance of TPH-2 mRNA was greater than TPH-1 mRNA. Serotonin as measured by ELISA increased 3-fold in the mature stage compared to the selection and expansion stages. In summary, a remarkably high percentage of cells derived from monkey ES cells exhibited neuronal plus serotonergic markers as well as nuclear steroid receptors similar to primate CNS serotonin neurons, suggesting that these cells may serve as a useful primate model for serotonergic neurons.
...
PMID:Serotonin neurons derived from rhesus monkey embryonic stem cells: similarities to CNS serotonin neurons. 1524 35

Insulin secretion from pancreatic beta cells is partly regulated by cell membrane potential. Background K+ channels that stabilize the resting membrane potential would suppress excitability and insulin secretion. Recent studies show that members of the two-pore domain K+ (K2P) channel family behave as background K+ channels in many excitable cells. Therefore, the expression of K2P channels was studied in insulin-secreting MIN6 cells. Reverse transcriptase PCR showed that, among nine K2P channels tested, TASK-1, TASK-2, TASK-3, TREK-2, and TRESK-2 were expressed in MIN6 cells. Cell-attached recordings on MIN6 cells revealed five types of K+ channels that were open at rest. Two were ATP-sensitive and Ca2+-activated K+ channels, as judged by their sensitivity to ATP and Ca2+, respectively, and single-channel conductance. Among five K2P channels, only TREK-2 could be clearly identified in MIN6 cells. The molecular identity of two other K+ channels is not yet known. TREK-2 in MIN6 cells was activated by arachidonic acid, membrane stretch, and low pH solution (pH 5.8). Arachidonic acid increased Ba2+-sensitive whole-cell current in MIN6 cell. These results suggest that TREK-2 contributes to the background K+ conductance in MIN6 cells, and may regulate depolarization-induced secretion of insulin.
...
PMID:Functional expression of TREK-2 in insulin-secreting MIN6 cells. 1535 40

An insulin-responsive element (IRE) in the rat angiotensinogen (ANG) gene promoter that binds to two nuclear proteins with apparent molecular weights of 48 and 70 kD was identified previously from rat immortalized renal proximal tubular cells (IRPTC). The present studies aimed to identify and clone the 48-kD nuclear protein and to define its action on ANG gene expression. Nuclear proteins were isolated from IRPTC and subjected to two-dimensional electrophoresis. The 48-kD nuclear protein was detected by Southwestern blotting and subsequently identified by mass spectrometry, revealing that it was identical to 46-kD heterogeneous nuclear ribonucleoprotein F (hnRNP F), a nuclear protein that binds to TATA-binding protein and associates with RNA polymerase II and also interacts with nuclear cap-binding complex. The hnRNP F cDNA was cloned from IRPTC by reverse transcriptase-PCR. Bacterially expressed recombinant hnRNP F bound to the rat ANG-IRE, as revealed by gel mobility shift assay. The addition of polyclonal antibodies against hnRNP F yielded a supershift in gel mobility. Transient transfer of sense and antisense hnRNP F cDNA in IRPTC inhibited and enhanced ANG gene expression, respectively. High glucose stimulated and insulin inhibited hnRNP F expression in IRPTC. Expression studies indicated that hnRNP F is present in the kidney, testis, liver, lung, and brain but not in the spleen. In conclusion, these studies demonstrate that hnRNP F binds to rANG-IRE and modulates renal ANG gene expression, implicating that dysregulation of hnRNP F might affect renin-angiotensin system activation and, subsequently, kidney injury in diabetes.
...
PMID:Heterogenous nuclear ribonucleoprotein F modulates angiotensinogen gene expression in rat kidney proximal tubular cells. 1565 59

The human epidermal growth factor receptor (EGFR) plays an oncogenic role in solid cancer, including brain primary and metastatic cancers. Transvascular nonviral gene therapy in combination with EGFR-RNA interference (RNAi) represents a new therapeutic approach to silencing oncogenic genes in solid cancers. This is achieved with pegylated immunoliposomes (PIL) carrying short hairpin RNA expression plasmids driven by the U6 RNA polymerase promoter and directed to target EGFR expression by RNAi. The PIL is comprised of a mixture of known lipids containing polyethyleneglycol (PEG), which stabilizes the PIL structure in vivo in circulation. The tissue target specificity of PILs is given by conjugation of approximately 1% of the PEG residues to monoclonal antibodies (mAbs) that bind to specific endogenous receptors (i.e., insulin and transferrin receptors) located in the brain vascular endothelium, which forms the blood brain barrier (BBB), and brain cellular membranes, respectively. These mAbs are known to induce 1) receptor-mediated transcytosis of the PIL complex through the BBB and 2) transport to the brain cell nuclear compartment. Treatment of an experimental human brain tumor model in scid mice is possible with weekly intravenous RNAi gene therapy causing reduced tumor expression of EGFR and 88% increase in survival time of these mice with advanced intracranial brain cancer. The availability of additional RNAi tumor targets may improve the therapeutic efficacy of this new anticancer drug. The accessibility to chimeric and/or humanized mAbs directed to human BBB and brain cell specific-receptors may accelerate the application of this technology to the treatment of human tumors.
...
PMID:RNA interference and nonviral targeted gene therapy of experimental brain cancer. 1571 65

We carry out an extensive statistical study of the applicability of normal modes to the prediction of mobile regions in proteins. In particular, we assess the degree to which the observed motions found in a comprehensive data set of 377 nonredundant motions can be modeled by a single normal-mode vibration. We describe each motion in our data set by vectors connecting corresponding atoms in two crystallographically known conformations. We then measure the geometric overlap of these motion vectors with the displacement vectors of the lowest-frequency mode, for one of the conformations. Our study suggests that the lowest mode contains useful information about the parts of a protein that move most (i.e., have the largest amplitudes) and about the direction of this movement. Based on our findings, we developed a Web tool for motion prediction (available from http://molmovdb.org/nma) and apply it here to four representative motions--from bacteriorhodopsin, calmodulin, insulin, and T7 RNA polymerase.
...
PMID:Normal modes for predicting protein motions: a comprehensive database assessment and associated Web tool. 1572 44

The homeodomain factor Pdx-1 regulates an array of genes in the developing and mature pancreas, but whether regulation of each specific gene occurs by a direct mechanism (binding to promoter elements and activating basal transcriptional machinery) or an indirect mechanism (via regulation of other genes) is unknown. To determine the mechanism underlying regulation of the insulin gene by Pdx-1, we performed a kinetic analysis of insulin transcription following adenovirus-mediated delivery of a small interfering RNA specific for pdx-1 into insulinoma cells and pancreatic islets to diminish endogenous Pdx-1 protein. insulin transcription was assessed by measuring both a long half-life insulin mRNA (mature mRNA) and a short half-life insulin pre-mRNA species by real-time reverse transcriptase-PCR. Following progressive knock-down of Pdx-1 levels, we observed coordinate decreases in pre-mRNA levels (to about 40% of normal levels at 72 h). In contrast, mature mRNA levels showed strikingly smaller and delayed declines, suggesting that the longer half-life of this species underestimates the contribution of Pdx-1 to insulin transcription. Chromatin immunoprecipitation assays revealed that the decrease in insulin transcription was associated with decreases in the occupancies of Pdx-1 and p300 at the proximal insulin promoter. Although there was no corresponding change in the recruitment of RNA polymerase II to the proximal promoter, its recruitment to the insulin coding region was significantly reduced. Our results suggest that Pdx-1 directly regulates insulin transcription through formation of a complex with transcriptional coactivators on the proximal insulin promoter. This complex leads to enhancement of elongation by the basal transcriptional machinery.
...
PMID:Mechanism of insulin gene regulation by the pancreatic transcription factor Pdx-1: application of pre-mRNA analysis and chromatin immunoprecipitation to assess formation of functional transcriptional complexes. 1574 69

Previous work has shown that the transcriptional regulator beta-catenin can translocate to the nuclei when cells are stimulated with the type 1 insulin-like growth factor (IGF-1). We show by immunocoprecipitation and by confocal microscopy that beta-catenin binds to and co-localizes with the insulin receptor substrate-1 (IRS-1), a docking protein for both the insulin and the IGF-1 receptors. IRS-1 is required for IGF-1-mediated nuclear translocation of beta-catenin, resulting in the activation of the beta-catenin target genes. IGF-1-mediated nuclear translocation of beta-catenin is facilitated by the nuclear translocation of IRS-1. Both IRS-1 and beta-catenin are recruited to the cyclin D1 promoter, an established target for beta-catenin, but only IRS-1 is recruited to the ribosomal DNA (rDNA) promoter. UBF proteins (known to interact with both IRS-1 and beta-catenin) are also detectable in the cyclin D1 and rDNA promoters. These results indicate that IRS-1 (activated by the IGF-1 receptor) is one of several proteins that regulate the subcellular localization and activity of beta-catenin. The ability of IRS-1 to localize to both RNA polymerase II (with beta-catenin) and RNA polymerase I-regulated promoters suggest an explanation for the effect of IRS-1 on both cell growth in size and cell proliferation. This possibility is supported by the demonstration that enforced nuclear localization of IRS-1 causes nuclear translocation of beta-catenin and transformation of normal mouse embryo fibroblasts (colony formation in soft agar).
...
PMID:Functional significance of type 1 insulin-like growth factor-mediated nuclear translocation of the insulin receptor substrate-1 and beta-catenin. 1596 2

Insulin-like growth factor-1 (IGF-1) is a member of a family of two interacting polypeptide hormone ligands with close homology to proinsulin. IGF-1 can influence mesenchymal cell migration, proliferation, and extracellular matrix deposition, thus implicating it in the progression of fibrotic disorders. Currently, there is limited information about the regulation of IGF-1 expression in areca quid-associated oral submucous fibrosis (OSF). The aim of this study was to compare IGF-1 expression in normal human buccal mucosa and OSF specimens and further explore the potential mechanism that may lead to induce IGF-1 expression. Twenty OSF specimens and 10 normal buccal mucosa were examined by immunohistochemistry. The activity of IGF-1 from cells cultured from OSF and normal buccal mucosa were by using reverse-transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Furthermore, the effect of arecoline, the major areca nut alkaloid, was added to explore the potential mechanism that may lead to induce IGF-1 expression. IGF-1 expression was significantly higher in OSF specimens (p<0.05) and expressed mainly by fibroblasts, endothelial cells, and inflammatory cells. OSF demonstrated significantly higher IGF-1 protein expression than normal buccal mucosa fibroblast (BMF) both in mRNA and protein levels (p<0.05). In addition, arecoline was also found to elevate IGF-1 mRNA and protein expression in a dose-dependent manner (p<0.05). Taken together, the data presented here demonstrated that IGF-1 expression is significantly upregulated in OSF from areca quid chewers and arecoline may be responsible for the enhanced IGF-1 expression in vivo.
...
PMID:The upregulation of insulin-like growth factor-1 in oral submucous fibrosis. 1605 26

Expression of the insulin gene is nearly exclusive to the beta cells of the pancreatic islets. Although the sequence-specific transcription factors that regulate insulin expression have been well studied, the interrelationship between these factors, chromatin structure, and transcriptional elongation by RNA polymerase II (pol II) has remained undefined. In this regard, recent studies have begun to establish a role for the methylation of histone H3 in the initiation or elongation of transcription by pol II. To determine a role for the transcriptional activator Pdx-1 in the maintenance of chromatin structure and pol II recruitment at the insulin gene, we performed small interfering RNA-mediated knockdown of Pdx-1 in betaTC3 cells and subsequently studied histone modifications and pol II recruitment by chromatin immunoprecipitation. We demonstrated here that the 50% fall in insulin transcription following knockdown of Pdx-1 is accompanied by a 60% fall in dimethylated histone H3-Lys-4 at the insulin promoter. H3-Lys-4 methylation at the insulin promoter may be mediated, at least partially, by the methyltransferase Set9. Immunohistochemical analysis revealed that Set9 is expressed in an islet-enriched pattern in the pancreas, similar to the pattern of Pdx-1 expression. The recruitment of Set9 to the insulin gene appears to be a consequence of its direct interaction with Pdx-1, and small interfering RNA-mediated knockdown of Set9 attenuates insulin transcription. Pdx-1 knockdown was also associated with an overall shift in the recruitment of pol II isoforms to the insulin gene, from an elongation isoform (Ser(P)-2) to an initiation isoform (Ser(P)-5). Our findings therefore suggest a model whereby Pdx-1 plays a novel role in linking H3-Lys-4 dimethylation and pol II elongation to insulin transcription.
...
PMID:Pdx-1 links histone H3-Lys-4 methylation to RNA polymerase II elongation during activation of insulin transcription. 1614 Dec 9


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

---