Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral neuropathy is an important complication of antiretroviral therapy. Nucleoside reverse-transcriptase inhibitor (NRTI)-associated mitochondrial dysfunction, inflammation and nutritional factors are implicated in its pathogenesis. Pharmacogenetic and genomic studies investigating NRTI neurotoxicity have only recently become possible via the linkage of HIV clinical studies to large DNA repositories. Preliminary case-control studies using these resources suggest that host mitochondrial DNA haplogroup polymorphisms in the hemochromatosis gene and proinflammatory cytokine genes may influence the risk of peripheral neuropathy during antiretroviral therapy. These putative risk factors await confirmation in other HIV-infected populations but they have strong biological plausibility. Work to identify underlying mechanisms for these associations is ongoing. Large-scale studies incorporating clearly defined and validated methods of neuropathy assessment and the use of novel laboratory models of NRTI-associated neuropathy to clarify its pathophysiology are now needed. Such investigations may facilitate the development of more effective strategies to predict, prevent and ameliorate this debilitating treatment toxicity in diverse clinical settings.
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PMID:Pharmacogenetics of nucleoside reverse-transcriptase inhibitor-associated peripheral neuropathy. 1937 18

Systemic iron homeostasis involves a negative feedback circuit in which the expression level of the peptide hormone hepcidin depends on and controls the iron blood levels. Hepcidin expression is regulated by the BMP6/SMAD and IL6/STAT signaling cascades. Deregulation of either pathway causes iron-related diseases such as hemochromatosis or anemia of inflammation. We quantitatively analyzed how BMP6 and IL6 control hepcidin expression. Transcription factor (TF) phosphorylation and reporter gene expression were measured under co-stimulation conditions, and the promoter was perturbed by mutagenesis. Using mathematical modeling, we systematically analyzed potential mechanisms of cooperative and competitive promoter regulation by the transcription factors, and experimentally validated the model predictions. Our results reveal that hepcidin cross-regulation primarily occurs by combinatorial transcription factor binding to the promoter, whereas signaling crosstalk is insignificant. We find that the presence of two BMP-responsive elements enhances the steepness of the promoter response towards the iron-sensing BMP signaling axis, which promotes iron homeostasis in vivo. IL6 co-stimulation reduces the promoter sensitivity towards the BMP signal, because the SMAD and STAT transcription factors compete for recruiting RNA polymerase to the transcription start site. This may explain why inflammatory signals disturb iron homeostasis in anemia of inflammation. Taken together, our results reveal why the iron homeostasis circuit is sensitive to perturbations implicated in disease.
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PMID:A multi-scale model of hepcidin promoter regulation reveals factors controlling systemic iron homeostasis. 2439 88