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:The mammary gland redeveloped to the pre-pregnancy state during involution, which shows that the mammary cells have the characteristics of remodeling. The rapidity and degree of mammary gland involution are different between mice and dairy livestock (dairy cows and dairy goats). However, the molecular genetic mechanism of involution and remodeling of goat mammary gland has not yet been clarified. Therefore, this study carried out the RNA-sequencing of nonlactating mammary gland tissue of dairy goats in order to reveal the transcriptome characteristics of nonlactating mammary tissues and clarify the molecular genetic mechanism of mammary cell involution and remodeling.
Project description:The mammary gland redeveloped to the pre-pregnancy state during involution, which shows that the mammary cells have the characteristics of remodeling. The rapidity and degree of mammary gland involution are different between mice and dairy livestock (dairy cows and dairy goats). However, the molecular genetic mechanism of miRNA in involution and remodeling of goat mammary gland has not yet been clarified. Therefore, this study carried out the RNA-sequencing of nonlactating mammary gland tissue of dairy goats in order to reveal the transcriptome characteristics of miRNA in nonlactating mammary tissues and clarify the molecular genetic mechanism of miRNA in mammary cell involution and remodeling.
Project description:Mammary gland branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases, MT1-MMP and MT2-MMP, that drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remains undefined. A mammary gland branching program that occurs during the first 10 days of early postnatal development was used to characterize the impact of global Mt1-mmp or Mt2-mmp targeting on mammary gland morphogenesis. Transcriptome profiling of ductal networks and associated stroma was used to investigate the functional roles of MT2-MMP in the early postnatal mammary gland in an unbiased fashion.
Project description:Mammary gland branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases, MT1-MMP and MT2-MMP, that drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remains undefined. A mammary gland branching program that occurs during the first 10 days of early postnatal development was used to characterize the impact of global Mt1-mmp or Mt2-mmp targeting on mammary gland morphogenesis. Transcriptome profiling of ductal networks and associated stroma was used to investigate the functional roles of MT1-MMP in the early postnatal mammary gland in an unbiased fashion.
Project description:Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. GM-CSF drives the generation of human monocyte-derived macrophages with a potent pro-inflammatory activity upon stimulation. Janus Kinase (JAK) inhibitors are small molecules that reversibly inhibit JAK activity and their subsequent intracellular signaling and have become the treatment of choice for diseases with an inflammatory or immune basis. We explored the molecular impact of blocking GM-CSFR-JAK2-STAT5 axis with the Janus Kinase (JAK) inhibitors Upadacitinib or Baricitinib on the gene expression profile in GM-CSF-primed human monocyte derived macrophages.
Project description:Mammary gland branching morphogenesis is thought to relie on the mobilization of the membrane-anchored matrix metalloproteinase, Mmp14/MT1-MMP, to drive mammary epithelial invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that this proteinase plays during postnatal mammary gland development in vivo remain undefined. A mammary gland branching program that occurs during the first 4 weeks of postnatal mouse development, in tandem with recently developed Mmp14-floxed mice and MMTV-Cre transgenics that express Cre recombinase throughout the mammary epithelial cell compartment, were used to characterize the impact of deleting epithelial cell Mmp14 on mammary gland morphogenesis. Transcriptome profiling of mammary epithelial cells was used to investigate the effects of MMTV-Cre expression on the postnatal mammary epithelial cell compartment in an unbiased fashion
Project description:Mammary gland branching morphogenesis is thought to relie on the mobilization of the membrane-anchored matrix metalloproteinase, Mmp14/MT1-MMP, to drive mammary epithelial invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that this proteinase plays during postnatal mammary gland development in vivo remain undefined. A mammary gland branching program that occurs during the first 4 weeks of postnatal mouse development, in tandem with recently developed Mmp14-floxed mice and MMTV-Cre transgenics that express Cre recombinase throughout the mammary epithelial cell compartment, were used to characterize the impact of deleting epithelial cell Mmp14 on mammary gland morphogenesis. Transcriptome profiling of mammary epithelial cells was used to investigate the functional roles of MT1-MMP in the postnatal mammary epithelial cell compartment in an unbiased fashion
Project description:Aberrant activation of oncogenic kinases is frequently observed in human cancers, but the underlying mechanism and resulting effects on global signaling are incompletely understood. Here, we demonstrate that the oncogenic FIP1L1-PDGFRa kinase exhibits a significantly different signaling pattern compared to PDGFRa wildtype: Interestingly, the conventional strong activation of PI3-kinase- and MAP-kinase- pathways is remarkably shifted towards a prominent activation of STAT factors. This diverging signaling pattern compared to classical PDGF-receptor signaling is partially coupled to the aberrant intracellular location of the oncogene, since membrane targeting of F/PDGFRa restores activation of MAPK- and PI3K-pathway completely. In contrast to the M-^SclassicalM-^T cytokine-induced STAT-activation process does STAT activation by F/PDGFR not require Janus kinase activity and does not involve a SH2-domain-mediated binding mechanism. Thus it is conceivable that STAT activation by F/PDGFR could be directly mediated by interaction of STAT factors with the kinase domain itself.