Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the Janus kinase (Jak) family of protein tyrosine kinases have recently been implicated in the proximal signal transduction events of cytokine receptors. Jak3, a newly discovered member of this family, is believed to be normally limited in its expression to cells of the lymphoid and myeloid lineages. Herein we show that Jak3 is expressed in primary human vascular cells, as well as other non-lymphoid and non-myeloid cell types. Reverse transcriptase-polymerase chain reaction and Northern blot analysis revealed that Jak3 mRNA was expressed at low levels in human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells (HASMC), A549 (human lung carcinoma), and DLD-1 (human colon adenocarcinoma) cells. Higher basal levels of Jak3 mRNA were detected in HMEC-1 (human microvascular cell line) and HepG2 (human hepatocellular carcinoma) cells. Jak3 mRNA expression was induced in HUVEC, HMEC-1, and HASMC by treatment with interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide. Jak3 protein was detectable at low levels in untreated HMEC-1, and these levels increased significantly with cytokine treatment. Furthermore, Jak3 protein was phosphorylated upon treatment of these cells with interleukin-4. This work shows that Jak3 is expressed or inducible in human vascular endothelial, vascular smooth muscle, and other non-lymphoid and non-myeloid cells, suggesting a broader role for Jak3 in the cytokine signal transduction of these cells.
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PMID:Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cells. 866 78

All pathogenic flaviviruses examined thus far inhibit host interferon (IFN) responses by suppressing the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Both Langat virus (LGTV; a member of the tick-borne encephalitis virus serogroup) and Japanese encephalitis virus use the nonstructural protein NS5 to suppress JAK-STAT signaling. However, NS5 is also critical to virus replication, contributing methyltransferase and RNA-dependent RNA polymerase (RdRP) activities. The specific amino acid residues of NS5 involved in IFN antagonism are not known. Here, we demonstrate that the LGTV NS5 JAK-STAT inhibitory domain is contained between amino acids 355 and 735 (of 903), a range which lies within the RdRP domain. Furthermore, we identified two noncontiguous stretches of specific amino acids within the RdRP, 374 to 380 and 624 to 647, as critical for inhibition of JAK-STAT signaling. Despite considerable separation on the linear NS5 sequence, these residues localized adjacent to each other when modeled on the West Nile virus RdRP crystal structure. Due to the general conservation of RdRP structures, these results suggest that the specific residues identified act cooperatively to form a unique functional site on the RdRP responsible for JAK-STAT inhibition. This insight into the mechanism underlying flavivirus IFN evasion strategies will facilitate the design of antiviral therapeutics that potentiate the action of IFN during infection.
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PMID:Identification of residues critical for the interferon antagonist function of Langat virus NS5 reveals a role for the RNA-dependent RNA polymerase domain. 1745 29

Current technologies for studying ion channels are fundamentally limited because of their inability to functionally link ion channel activity to cellular pathways. Herein, we report the use of label-free cell phenotypic profiling to decode the composition and signaling of an endogenous ATP-sensitive potassium ion channel (KATP) in HepG2C3A, a hepatocellular carcinoma cell line. Label-free cell phenotypic agonist profiling showed that pinacidil triggered characteristically similar dynamic mass redistribution (DMR) signals in A431, A549, HT29 and HepG2C3A, but not in HepG2 cells. Reverse transcriptase PCR, RNAi knockdown, and KATP blocker profiling showed that the pinacidil DMR is due to the activation of SUR2/Kir6.2 KATP channels in HepG2C3A cells. Kinase inhibition and RNAi knockdown showed that the pinacidil activated KATP channels trigger signaling through Rho kinase and Janus kinase-3, and cause actin remodeling. The results are the first demonstration of a label-free methodology to characterize the composition and signaling of an endogenous ATP-sensitive potassium ion channel.
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PMID:Label-free cell phenotypic profiling decodes the composition and signaling of an endogenous ATP-sensitive potassium channel. 2481 92

SARS-CoV-2 is the most recent coronavirus which crossed the species barrier in 2019 and provoked a still ongoing and dangerous pandemic known as coronavirus disease 2019 (COVID-19). The SARS-CoV-2 infection has triggered an impressive amount of clinical and experimental studies to identify an effective and safe therapy to stop the pandemic spread. Hence, numerous trials and studies have scrutinized the analogies between SARS-CoV-2 and other corona viruses or the host-virus interactions and their similarities with immune system disorders. Still, the pathogenic mechanisms behind SARS-CoV-2 have been partially deciphered and the current therapies have not yet met the initial enthusiastic expectations. So far COVID-19 therapies have targeted various pathogenic mechanisms, namely the neutralization of ACE2 receptors or SARS-CoV-2 spike protein epitopes, the disruption of the endocytic pathways using hydroxychloroquine, arbidol, or anti-Janus kinase inhibitors, the inhibition of RNA-dependent RNA polymerase using nucleotide analogues such as remdesivir, immunosuppressive drugs or molecules acting on the immune response (corticoids, interferons, monoclonal antibodies against inflammatory cytokines, mesenchymal stem cells) and convalescent plasma administration together with numerous drugs with unproven effect against SARS-CoV-2 but with potential antiviral activities (antiretrovirals, antimalarial drugs, antibiotics, etc.). Nevertheless, these therapies have been associated with side effects and contradictory results. At the same time a specific SARS-CoV-2 vaccine is a long-term solution requiring clinical validation and important investments together with appropriate strategies to promote the confidence in the safety of the new vaccine. The article revises the current state of SARS-CoV-2 therapeutic options but advises towards a more cautious and individualized treatment approach centred on the clinical features, immune particularities, and the risk-benefit balance.
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PMID:SARS-CoV-2 Treatment Approaches: Numerous Options, No Certainty for a Versatile Virus. 3298 20