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.
Project description:Safe and efficient antibacterial materials are urgently needed to combat drug-resistant bacteria and biofilm-associated infections. The rational design of nanoparticles for flexible elimination of biofilms by alternative strategies remains challenging. Herein, we propose the fabrication of Janus-structured nanoparticles targeting extracellular polymeric substance to achieve dispersion or near-infrared (NIR) light-activated photothermal elimination of drug-resistant biofilms, respectively. Asymmetrical Janus-structured dextran-bismuth selenide (Dex-BSe) nanoparticles are fabricated by a facile strategy to exploit synergistic effects of both components. The biocompatible dextran domain with the maximum exposure endows the Janus nanoparticles with biofilm penetration, targeting, and dispersion functions. Interestingly, Janus Dex-BSe nanoparticles realize enhanced dispersal of biofilms over time compared with dextran nanoparticles while the underlying molecular mechanisms are further revealed by RNA-sequencing transcriptomics analysis. Alternatively, taking advantage of the preferential accumulation of nanoparticles at infection sites, the self-propelled active motion induced by the unique Janus structure enhances the photothermal killing effect under NIR light irradiation, thereby eradicating the biofilm. Given these favorable features, the antibiofilm activity of Janus Dex-BSe against methicillin-resistant Staphylococcus aureus (MRSA) was first validated in vitro. More importantly, the flexible application of Janus Dex-BSe nanoparticles for biofilm removal or NIR-triggered eradication in vivo was demonstrated by MRSA-infected mouse excisional wound model and abscess model, respectively. The currently developed Janus nanoplatform holds great promise for the efficient elimination of drug-resistant biofilms in diverse antibacterial scenarios.
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.
Project description:Symptomatic previously untreated chronic lymphocytic leukemia patients were treated with the janus kinase (JAK)-inhibitor ruxolitinib (clinicaltrials.gov, number NCT02015208). CLL cells from 6 of the patients were purified prior to commencing ruxolitinib and again 4 or 8 weeks after treatment and analyzed by RNAseq. Ruxolitinib induced a stereotyped response in all patients consisting of a rapid decrease in palpable lymphadenopathy accompanied by increased lymphocytosis and blood lactate dehydrogenase. This response was associated with evidence of inhibited JAK-signaling in CLL cells but activation of other oncogenic pathways.