Cardiomyocyte Janus Kinase 1 (JAK1) Signaling is Required for Cardiac Homeostasis and Cytokine-Dependent Activation of STAT3
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ABSTRACT:
PROVIDER: PRJNA1273004 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33872989_1.fastq.gz | Fastqsanger.gz | |||
| SRR33872989_2.fastq.gz | Fastqsanger.gz | |||
| SRR33872990_1.fastq.gz | Fastqsanger.gz | |||
| SRR33872990_2.fastq.gz | Fastqsanger.gz | |||
| SRR33872991_1.fastq.gz | Fastqsanger.gz |
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Project description:Cytokine receptors respond to circulating inflammatory cytokines by signaling through Janus kinases (JAK) to ultimately elicit phosphorylation-dependent nuclear translocation and transcriptional activity of signal transducer and activator of transcription (STAT) proteins. JAK1 is particularly important for STAT3-dependent cytokine production and macrophage recruitment by cardiomyocytes, however the role of basal JAK1 signaling in cardiac homeostasis remains unclear. Downstream signaling through STAT3 promotes cardiac hypertrophy and remodeling in response to pressure overload or angiotensin-II but is protective during ischemic injury. To assess the roles of JAK1 in cardiac physiology we generated mice with cardiomyocyte-specific deletion of JAK1 and evaluated cardiac structure and function, myocardial remodeling, and intracellular signal transduction. Loss of JAK1 in cardiomyocytes results in dilated cardiomyopathy by 6 months of age, indicating cytokine receptor signaling through JAK1 is essential for cardiac physiology. Cardiomyopathy in aged mice lacking cardiomyocyte JAK1 was characterized by substantial myocardial fibrosis. Transcriptomics and gene expression analyses identified JAK1-dependent cytokine-inducible target genes in adult cardiomyocytes. JAK1-deficient cardiomyocytes were resistant to phosphorylation and nuclear translocation of STAT3 and transcriptional reprogramming in response to the cytokine oncostatin M. Collectively these data indicate cardiomyocyte JAK1 kinase activity is required for proper cardiac maturation and homeostasis and is indispensable for STAT3 activation by oncostatin M.
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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.
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Project description:Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. Somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis; We used microarray to compare the gene expression profile of JAK1 mutation positive or negative ALL blasts Experiment Overall Design: Thawed or freshly isolated T-ALL cells (>90% blasts) were homogenized, total RNA was extracted and hybridized on Affymetrix microarrays
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Project description:Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. Somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis We used microarray to compare the gene expression profile of JAK1 mutation positive or negative ALL blasts
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Project description:Inflammatory cytokines promote the development of pancreatic ductal adenocarcinoma (PDAC), but the functions of specific intracellular signaling mediators in this process are less well-defined. In this study, we discovered that the Janus kinase 1 (JAK1) is critical for the early postnatal growth of the exocrine pancreas. Using a ligand-controlled and pancreas-specific knockout in adult mice, we demonstrate that JAK1 deficiency prevents the formation of KRASG12D-induced pancreatic tumors, and we established that JAK1 is essential for the constitutive activation of STAT3 whose activation is a prominent characteristic of PDAC. We identified C/EBPδ as a biologically relevant downstream target of JAK1 signaling, which is upregulated in human PDAC. Reinstating the expression of C/EBPδ was sufficient to rescue the growth of JAK1-deficient tumorspheres. Collectively, the findings of this study suggest that JAK1 executes important functions of inflammatory cytokines through C/EBPδ and may serve as a molecular target for PDAC prevention and treatment.
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