Janus kinase-Inhibition modulates hepatitis E virus infection
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ABSTRACT:
PROVIDER: PRJNA932725 | ENA |
REPOSITORIES: ENA
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Project description:Background: Human hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of infection. Janus kinase (JAK) inhibitors (JAKi) are a novel drug class for the treatment of autoimmune inflammatory rheumatic disease (AIRD). As JAKs play a key role in innate immunity, viral infections and reactivations are frequently reported during JAKi treatment in AIRD patients. The aim of this study was to characterize the influence of JAKis on HEV replication in vivo and in authentic cell culture models ex vivo. Methods: We evaluated liver enzymes of an AIRD patient under JAKi therapy with hepatitis E and HEV infections in a cohort of AIRD patients. Experiments with HEV were performed by infection of primary human hepatocytes (PHHs) followed by immunofluorescence staining of viral markers and transcriptomic analysis. Results: Acute hepatitis was observed in a patient with AIRD and concomitant HEV infection. No acute infection could be detected in the AIRD cohort. Infection experiments in PHHs displayed an up to 50-fold increase of progeny virus production during JAKi treatment and transcriptomic analysis revealed induction of antiviral programs during infection. This induction was perturbed in the presence of JAKis, concomitant with elevated HEV RNA levels. Conclusion: Therapeutic JAK inhibition increases HEV replication by modulating the HEV-triggered immune response. Therefore, clinical monitoring of HEV infection during JAKi treatment and in case of elevated liver enzymes should be considered.
2023-02-09 | GSE224795 | GEO
Project description:Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition
| PRJNA778250 | ENA
Project description:Janus kinases (JAKs) and their downstream STAT proteins play key roles in cytokine signaling, tissue homeostasis, and cancer development. Using a novel breast cancer model that conditionally lacks the Janus kinase 1, we show here that JAK1 is essential for IL-6 class inflammatory cytokine signaling and plays a critical role in metastatic cancer progression. JAK1 is indispensable for the oncogenic activation of STAT1, STAT3, and STAT6 in ERBB2-expressing cancer cells, suggesting that ERBB2 receptor tyrosine kinase complexes do not directly activate these STAT proteins in vivo. A genome-wide gene expression analysis revealed that JAK1 signaling has pleiotropic effects on several pathways associated with cancer progression. We established that FOS and MAP3K8 are targets of JAK1/STAT3 signaling that promote tumorsphere formation and cell migration. The results highlight the significance of JAK1 as a rational therapeutic target to block IL-6 class cytokines that are master regulators of cancer-associated inflammation.
2019-03-27 | GSE121064 | GEO
Project description:FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia
| PRJNA1020175 | ENA
Project description:Janus kinase 1 plays a critical role in mammary cancer progression
| PRJNA495488 | ENA
Project description:MicroRNAs (miRNAs) are important regulators of gene expression. Their levels are precisely controlled through modulating the activity of the microprocesser complex (MC). Here we report that JANUS, a homology of the conserved U2 snRNP assembly factor in yeast and human, is required for miRNA accumulation. JANUS associates with MC components Dicer-like 1 and SERRATE (SE) and directly binds the stem-loop of pri-miRNAs. In a hypomorphic janus mutant, the activity of DCL1, the numbers of MC, and the interaction of primary miRNA transcript (pri-miRNAs) with MC are reduced. These data suggest that JANUS promotes the assembly and activity of MC through its interaction with MC and/or pri-miRNAs. In addition, JANUS modulates the transcription of some pri-miRNAs as it binds the promoter of pri-miRNAs and promotes Pol II occupancy of at their promoters. Moreover, global splicing defects are detected in janus. Taken together, our study reveals a novel role of a conserved splicing factor in miRNA biogenesis.
2023-06-01 | GSE229519 | GEO
Project description:PIM kinase inhibition in HCC xenograft
| PRJNA598723 | ENA
Project description:Impairment of hepatic growth hormone (GH)- janus kinase (JAK) 2- signal transducer and activator of transcription (STAT) 5 signaling is associated with non-alcoholic fatty liver disease, while persistently high levels of GH can result in hepatic inflammation and liver cancer. Despite its anti-steatotic functions, STAT5 in hepatocytes has been implicated to be a tumor suppressor, whose loss strongly accelerates tumor formation in the presence of high GH levels. Yet, it remains unclear whether the upstream kinase JAK2 exerts similar tumor-suppressive functions. To address this question, we crossed a mouse model of inflammatory liver cancer (GHtg) to mice harboring the hepatocyte-specific deletion of JAK2 (JAK2Îhep) and compared them to GHtgSTAT5Îhep mice. We show that JAK2 deficiency in the GHtg background resulted in profound steatosis at young age due to ectopic lipid redistribution and increased hepatic de novo lipogenesis. Generation of reactive oxygen species (ROS) was increased in all genotypes compared to wildtype controls, while DNA damage and lipid peroxidation were observed only in GHtg and GHtgSTAT5Îhep animals. Importantly, Affymetrix analysis revealed that the expression of glutathione S-transferases (GSTs), a major group of detoxification enzymes, was strongly upregulated in JAK2 deficient livers. In vitro and in vivo studies further confirmed that ruxolitinib-mediated inhibition of JAK2 led to significant upregulation of GSTs, indicating a direct involvement of JAK2 in the negative regulation of these genes. Strikingly, despite equally profound hepatosteatosis and ROS production as in GHtgSTAT5Îhep mice, loss of JAK2 significantly delayed tumor formation in GHtg mice. Conclusion: Thus, in absence of hepatic JAK2, mice were protected against elevated ROS-induced DNA damage and lipid peroxidation through significant expression of GSTs.
2016-10-01 | E-MTAB-3774 | biostudies-arrayexpress