Search results for " Regulator"
showing 10 items of 728 documents
Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas
2017
Abstract Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n = 1,289) between microdissected FDCs and fibroblasts. Supervised analysis comparing FDC sarcomas with mi…
Peripheral artery disease, redox signaling, oxidative stress – Basic and clinical aspects
2017
Reactive oxygen and nitrogen species (ROS and RNS, e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. At higher concentrations, ROS and RNS lead to oxidative stress and oxidative damage of biomolecules (e.g. via formation of peroxynitrite, fenton chemistry). Peripheral artery disease (PAD) is characterized by severe ischemic conditions in the periphery leading to intermittent claudication and critical limb ischemia (end stage). It is well known that redox biology and oxidative stress play an important role in this setting. We here discuss the major pathways of oxidative stress and re…
Disruption of the CCL1-CCR8 axis inhibits vascular Treg recruitment and function and promotes atherosclerosis in mice
2019
The CC chemokine 1 (CCL1, also called I-309 or TCA3) is a potent chemoattractant for leukocytes that plays an important role in inflammatory processes and diseases through binding to its receptor CCR8. Here, we investigated the role of the CCL1-CCR8 axis in atherosclerosis. We found increased expression of CCL1 in the aortas of atherosclerosis-prone fat-fed apolipoprotein E (Apoe)-null mice; moreover, in vitro flow chamber assays and in vivo intravital microscopy demonstrated an essential role for CCL1 in leukocyte recruitment. Mice doubly deficient for CCL1 and Apoe exhibited enhanced atherosclerosis in aorta, which was associated with reduced plasma levels of the anti-inflammatory interle…
Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy
2016
Peripheral or central nerve injury is a frequent cause of chronic pain and the mechanisms are not fully understood. Using newly generated transgenic mice we show that progranulin overexpression in sensory neurons attenuates neuropathic pain after sciatic nerve injury and accelerates nerve healing. A yeast-2-hybrid screen revealed putative interactions of progranulin with autophagy-related proteins, ATG12 and ATG4b. This was supported by colocalization and proteomic studies showing regulations of ATG13 and ATG4b and other members of the autophagy network, lysosomal proteins and proteins involved in endocytosis. The association of progranulin with the autophagic pathway was functionally confi…
Dynamics and predicted drug response of a gene network linking dedifferentiation with β-catenin dysfunction in hepatocellular carcinoma
2019
Background & Aims Alterations of individual genes variably affect the development of hepatocellular carcinoma (HCC). Thus, we aimed to characterize the function of tumor-promoting genes in the context of gene regulatory networks (GRNs). Methods Using data from The Cancer Genome Atlas, from the LIRI-JP (Liver Cancer – RIKEN, JP project), and from our transcriptomic, transfection and mouse transgenic experiments, we identify a GRN which functionally links LIN28B-dependent dedifferentiation with dysfunction of β-catenin (CTNNB1). We further generated and validated a quantitative mathematical model of the GRN using human cell lines and in vivo expression data. Results We found that LIN28B and C…
Mast cells contribute to autoimmune diabetes by releasing interleukin-6 and failing to acquire a tolerogenic IL-10+ phenotype
2017
Mast cells (MCs) are innate immune cells that exert positive and negative immune modulatory functions capable to enhance or limit the intensity and/or duration of adaptive immune responses. Although MCs are crucial to regulate T cell immunity, their action in the pathogenesis of autoimmune diseases is still debated. Here we demonstrate that MCs play a crucial role in T1D pathogenesis so that their selective depletion in conditional MC knockout NOD mice protects them from the disease. MCs of diabetic NOD mice are overly inflammatory and secrete large amounts of IL-6 that favors differentiation of IL-17-secreting T cells at the site of autoimmunity. Moreover, while MCs of control mice acquire…
Temporal quantitative phosphoproteomics of ADP stimulation reveals novel central nodes in platelet activation and inhibition
2017
Adenosine diphosphate (ADP) enhances platelet activation by virtually any other stimulant to complete aggregation. It binds specifically to the G-protein-coupled membrane receptors P2Y1 and P2Y12, stimulating intracellular signaling cascades, leading to integrin aIIbb3 activation, a process antagonized by endothelial prostacyclin. P2Y12 inhibitors are among the most successful antiplatelet drugs, however, show remarkable variability in efficacy. We reasoned whether a more detailed molecular understanding of ADP-induced protein phosphorylation could identify (1) critical hubs in platelet signaling toward aggregation and (2) novel molecular targets for antiplatelet treatment strategies. We ap…
Reciprocal regulation of the Il9 locus by counteracting activities of transcription factors IRF1 and IRF4.
2017
The T helper 9 (Th9) cell transcriptional network is formed by an equilibrium of signals induced by cytokines and antigen presentation. Here we show that, within this network, two interferon regulatory factors (IRF), IRF1 and IRF4, display opposing effects on Th9 differentiation. IRF4 dose-dependently promotes, whereas IRF1 inhibits, IL-9 production. Likewise, IRF1 inhibits IL-9 production by human Th9 cells. IRF1 counteracts IRF4-driven Il9 promoter activity, and IRF1 and IRF4 have opposing function on activating histone modifications, thus modulating RNA polymerase II recruitment. IRF1 occupancy correlates with decreased IRF4 abundance, suggesting an IRF1-IRF4-binding competition at the I…
Expression of regulatory genes in the embryonic brain of a lizard and implications for understanding pallial organization and evolution
2017
The comparison of gene expression patterns in the embryonic brain of mouse and chicken is being essential for understanding pallial organization. However, the scarcity of gene expression data in reptiles, crucial for understanding evolution, makes it difficult to identify homologues of pallial divisions in different amniotes. We cloned and analyzed the expression of the genes Emx1, Lhx2, Lhx9, and Tbr1 in the embryonic telencephalon of the lacertid lizard Psammodromus algirus. The comparative expression patterns of these genes, critical for pallial development, are better understood when using a recently proposed six-part model of pallial divisions. The lizard medial pallium, expressing all…
Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance
2016
International audience; Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemoth…