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Etienne Wang, Sivan Harel, Angela M Christiano
Legrand et al show that JAK/STAT5 signaling in the dermal papilla is required for anagen onset in the murine hair cycle. Interestingly, others have shown that JAK-inhibition is able to induce telogen-to-anagen transition in wild-type mice. This apparent contradiction highlights the complexity of interactions within the hair follicle, and encourages further discussion on the role of JAK-STAT signaling in the various stem cell niches of the hair follicle.
November 2016: Journal of Investigative Dermatology
Kristine Moltu, Karen Henjum, Nikolaus G Oberprieler, Bjørn A Bjørnbeth, Kjetil Taskén
Patients with colorectal cancer (CRC) have been shown to have elevated levels of circulating prostaglandin E2(PGE2) which promotes cancer progression and suppresses T-cell immune responses. In this study we evaluated whether signaling responses in T lymphocytes obtained from peripheral blood of CRC patients were affected by the sustained exposure to increased levels of PGE2. The phosphorylation status of an extended panel of proteins involved in downstream signaling cascades in T cells was profiled at a single cell level both in naïve and antigen-experienced cells after triggering T cell-, prostaglandin- and interleukin-2 receptors...
October 18, 2016: Human Immunology
Elizabeth E Hjort, Weiqi Huang, Liping Hu, Elizabeth A Eklund
Icsbp/Irf8 is an interferon regulatory transcription factor that functions as a suppressor of myeloid leukemias. Consistent with this activity, Icsbp represses a set of genes encoding proteins that promote cell proliferation/survival. One such gene encodes Gas2, a calpain inhibitor. We previously found that increased Gas2-expression in Bcr-abl+ cells stabilized βcatenin; a Calpain substrate. This was of interest, because βcatenin contributes to disease progression in chronic myeloid leukemia (CML). Calpain has additional substrates implicated in leukemogenesis, including Stat5...
October 19, 2016: Oncotarget
Xiuqing Tian, Rui Guo, Yujiao Zhang, Lingling Xu, Xianbing Liu, Yinglong Hou
OBJECTIVE: To observe the effects of sympathetic overactivity on the immune system involved in the imbalance of T helper (Th) lymphocytes, we investigated the correlation between autonomic dysregulation and the generation of regulatory T (Treg) and Th1 chemokines in patients with acute coronary syndrome (ACS). METHODS: Blood samples obtained from patients with coronary artery disease and controls were analyzed for levels of Th1 and Treg cells and their associated cytokines by flow cytometry...
October 21, 2016: Neuroimmunomodulation
Sophia Pinz, Anne Rascle
Transcriptional activation by STAT5 is repressed by deacetylase inhibitors. Investigating the role of deacetylases (HDACs) in STAT5-mediated transcription implies the analysis of molecular events taking place at the chromatin level. We describe here two alternative methods of chromatin immunoprecipitation that allow the characterization of chromatin modifications ensuing STAT5 activation and its inhibition by deacetylase inhibitors, in particular changes in histone acetylation, in histone occupancy, and in the association/dissociation of transcription factors and other chromatin-associated factors...
2017: Methods in Molecular Biology
Himalee S Sabnis, Heath L Bradley, Shweta Tripathi, Wen-Mei Yu, William Tse, Cheng-Kui Qu, Kevin D Bunting
Current therapy for acute myeloid leukemia (AML) primarily includes high-dose cytotoxic chemotherapy with or without allogeneic stem cell transplantation. Targeting unique cellular metabolism of cancer cells is a potentially less toxic approach. Monotherapy with mitochondrial inhibitors like metformin have met with limited success since escape mechanisms such as increased glycolytic ATP production, especially in hyperglycemia, can overcome the metabolic blockade. As an alternative strategy for metformin therapy, we hypothesized that the combination of 6-benzylthioinosine (6-BT), a broad-spectrum metabolic inhibitor, and metformin could block this drug resistance mechanism...
October 5, 2016: Leukemia Research
Dirk Fahrenkamp, Jinyu Li, Sabrina Ernst, Hildegard Schmitz-Van de Leur, Nicolas Chatain, Andrea Küster, Steffen Koschmieder, Bernhard Lüscher, Giulia Rossetti, Gerhard Müller-Newen
STAT5 is an essential transcription factor in hematopoiesis, which is activated through tyrosine phosphorylation in response to cytokine stimulation. Constitutive activation of STAT5 is a hallmark of myeloid and lymphoblastic leukemia. Using homology modeling and molecular dynamics simulations, a model of the STAT5 phosphotyrosine-SH2 domain interface was generated providing first structural information on the activated STAT5 dimer including a sequence, for which no structural information is available for any of the STAT proteins...
October 18, 2016: Scientific Reports
Toru Hosoi, Yuka Suyama, Takaaki Kayano, Koichiro Ozawa
Leptin resistance is one of the mechanisms involved in the pathophysiology of obesity. The present study showed that glucose deprivation inhibited leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) and signal transducer and activator of transcription 5 (STAT5) in neuronal cells. Flurbiprofen reversed glucose deprivation-mediated attenuation of STAT3, but not STAT5 activation, in leptin-treated cells. Glucose deprivation increased C/EBP-homologous protein and glucose regulated protein 78 induction, indicating the activation of unfolded protein responses (UPR)...
2016: Frontiers in Pharmacology
Shotaro Ando, Jun-Ichi Kawada, Takahiro Watanabe, Michio Suzuki, Yoshitaka Sato, Yuka Torii, Masato Asai, Fumi Goshima, Takayuki Murata, Norio Shimizu, Yoshinori Ito, Hiroshi Kimura
Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model...
October 8, 2016: Oncotarget
Carmen Burtea, Sophie Laurent, Tuba Sanli, Deborah Fanfone, Aude Devalckeneer, Sébastien Sauvage, Marie-Claire Beckers, Sandrine Rorive, Isabelle Salmon, Luce Vander Elst, Bernard R Lauwerys, Robert N Muller
BACKGROUND: Interleukin-7 receptor alpha (IL-7Rα) represents a biomarker with potential applications in rheumatoid arthritis (RA) diagnosis and therapy. We have therefore searched by phage display potential IL-7Rα specific peptides with the primary goal being to develop in vivo molecular imaging tools. METHODS: IL-7Rα-targeted peptides were searched within a disulfide-constrained combinatorial phage displayed library of random linear heptapeptides. The apparent dissociation constant (Kd) and half maximal inhibition constant (IC50) were estimated for phage clones and synthesized peptides by ELISA...
October 12, 2016: Arthritis Research & Therapy
Suchismita Daw, Ritam Chatterjee, Aditya Law, Sujata Law
Hematological disorders like myelodysplastic syndrome (MDS) may arise due to cumulative dysregulation of various signalling pathways controlling proliferation, differentiation, maturation and apoptosis of bone marrow cells. This devastating bone marrow condition can be due to consequential abnormalities in haematopoiesis as well as its supportive microenvironment. Although mutations related to JAK/STAT pathway are common in myeloproliferative neoplasms, further studies are required to fully explore the myelodysplastic scenario regarding the concerned pathway...
October 7, 2016: Chemico-biological Interactions
Madeleine Themanns, Kristina M Mueller, Sonja M Kessler, Nicole Golob-Schwarzl, Thomas Mohr, Doris Kaltenecker, Jerome Bourgeais, Jamile Paier-Pourani, Katrin Friedbichler, Doris Schneller, Michaela Schlederer, Eva Zebedin-Brandl, Luigi M Terracciano, Xiaonan Han, Lukas Kenner, Kay-Uwe Wagner, Wolfgang Mikulits, Andrey V Kozlov, Markus H Heim, Fabrice Gouilleux, Johannes Haybaeck, Richard Moriggl
Genetic deletion of the tyrosine kinase JAK2 or the downstream transcription factor STAT5 in liver impairs growth hormone (GH) signalling and thereby promotes fatty liver disease. Hepatic STAT5 deficiency accelerates liver tumourigenesis in presence of high GH levels. To determine whether the upstream kinase JAK2 exerts similar functions, we crossed mice harbouring a hepatocyte-specific deletion of JAK2 (JAK2(Δhep)) to GH transgenic mice (GH(tg)) and compared them to GH(tg)STAT5(Δhep) mice. Similar to GH(tg)STAT5(Δhep) mice, JAK2 deficiency resulted in severe steatosis in the GH(tg) background...
October 7, 2016: Scientific Reports
Xin Xu, Kunkun Han, Jingyu Zhu, Hongwu Mao, Xu Lin, Zubin Zhang, Biyin Cao, Yuanying Zeng, Xinliang Mao
The activated JAK2-STAT3 signaling pathway is a high risk factor for multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, SC09, a potential inhibitor of cholesterol absorption, was identified in a STAT3-targeted drug screen. SC09 suppressed the activation of STAT3 in a time-course and concentration-dependent manner but did not affect its family members STAT1 and STAT5. SC09 inhibited STAT3 transcriptional activity and downregulated the expression of STAT3-regulated genes. Further studies showed that SC09 selectively inhibited JAK2 activation but not other kinases including c-Src, ERK, p38 and mTOR that are all associated with STAT3 activation...
September 26, 2016: Oncotarget
Adam Ceroi, David Masson, Anne Roggy, Christophe Roumier, Cécile Chagué, Thierry Gauthier, Laure Philippe, Baptiste Lamarthée, Fanny Angelot-Delettre, Francis Bonnefoy, Sylvain Perruche, Sabeha Biichle, Claude Preudhomme, Elisabeth Macintyre, Laurent Lagrost, Francine Garnache-Ottou, Philippe Saas
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from plasmacytoid dendritic cells (PDC). No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared to those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDC. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes...
October 4, 2016: Blood
Michaela Willi, Kyung Hyun Yoo, Chaochen Wang, Zlatko Trajanoski, Lothar Hennighausen
Cytokines utilize the transcription factor STAT5 to control cell-specific genes at a larger scale than universal genes, with a mechanistic explanation yet to be supplied. Genome-wide studies have identified putative STAT5-based mammary-specific and universal enhancers, an opportunity to investigate mechanisms underlying their differential response to cytokines. We have now interrogated the integrity and function of both categories of regulatory elements using biological and genetic approaches. During lactation, STAT5 occupies mammary-specific and universal cytokine-responsive elements...
September 30, 2016: Nucleic Acids Research
Pei Wu, Wei-Dan Jiang, Jun Jiang, Juan Zhao, Yang Liu, Yong-An Zhang, Xiao-Qiu Zhou, Lin Feng
This study investigated the effects of choline on intestinal mucosal immune and the possible mechanisms in fish by feeding juvenile Jian carp (Cyprinus carpio var. Jian) with graded levels of dietary choline (165-1820 mg/kg diet) for 65 days. The results firstly showed that choline deficiency induced inflammatory infiltration in the proximal intestine (PI), mid intestine (MI) and distal intestine (DI) of fish. Meanwhile, compared with the optimal choline group, choline deficiency decreased the activities of lysozyme and acid phosphatase, contents of complement 3 and IgM in the intestine, downregulated the mRNA levels of antimicrobial peptides (liver-expressed antimicrobial peptide (LEAP) 2A and defensin-3 in the PI and MI, LEAP-2B and hepcidin in the PI, MI and DI), anti-inflammatory cytokines (interleukin (IL) 10 and transforming growth factor β2 in the PI, MI and DI), and signaling molecule IκB in the PI, MI and DI; while upregulated the mRNA levels of pro-inflammatory cytokines (IL-6a and tumor necrosis factor α in the MI and DI, interferon γ2b in the PI and MI, IL-1β and IL-6b in the PI, MI and DI), and signaling molecules (Toll-like receptor 4 in the MI, myeloid differentiation primary response 88 in the PI and MI, Janus kinase 3 and tyrosine kinase 2 in the MI and DI, nuclear factor kappa B (NF-κB), signal transducers and activators of transcription (STAT) 4 and STAT5 in the PI, MI and DI) of juvenile Jian carp, further indicating that choline deficiency caused inflammation and immunity depression in the intestine of fish...
September 28, 2016: Fish & Shellfish Immunology
Obi L Griffith, Szeman Ruby Chan, Malachi Griffith, Kilannin Krysiak, Zachary L Skidmore, Jasreet Hundal, Julie A Allen, Cora D Arthur, Daniele Runci, Mattia Bugatti, Alexander P Miceli, Heather Schmidt, Lee Trani, Krishna-Latha Kanchi, Christopher A Miller, David E Larson, Robert S Fulton, William Vermi, Richard K Wilson, Robert D Schreiber, Elaine R Mardis
Estrogen receptor alpha-positive (ERα+) luminal tumors are the most frequent subtype of breast cancer. Stat1(-/-) mice develop mammary tumors that closely recapitulate the biological characteristics of this cancer subtype. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of Stat1(-/-) primary mammary tumors and matched normal tissues. This investigation identified somatic truncating mutations affecting the prolactin receptor (PRLR) in all tumor and no normal samples...
September 27, 2016: Cell Reports
D T Saenz, W Fiskus, T Manshouri, K Rajapakshe, S Krieger, B Sun, C P Mill, C DiNardo, N Pemmaraju, T Kadia, S Parmar, S Sharma, C Coarfa, P Qiu, S Verstovsek, K N Bhalla
Myeloproliferative Neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of JAK-STAT signaling, which responds to treatment with the JAK1 & 2 kinase inhibitor (JAKi) ruxolitinib. However, MPN-MF often progresses (~20%) to secondary AML (sAML), where standard induction chemotherapy or ruxolitinib is relatively ineffective, necessitating the development of novel therapeutic approaches. In the present studies, we demonstrate that treatment with BET (bromodomain and extra terminal) protein inhibitor (BETi), e...
September 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Ashok Kumar Jayavelu, Jennifer N Moloney, Frank-D Böhmer, Thomas G Cotter
In different types of myeloid leukemia, increased formation of reactive oxygen species (ROS) has been noted and associated with aspects of cell transformation, including the promotion of leukemic cell proliferation and migration, as well as DNA damage and accumulation of mutations. Work reviewed in this article has revealed the involvement of NADPH oxidase (NOX)-derived ROS downstream of oncogenic protein-tyrosine kinases in both processes, and the related pathways have been partially identified. FMS-like tyrosine kinase 3 with internal tandem duplications (FLT3-ITD), an important oncoprotein in a subset of acute myeloid leukemias, causes activation of AKT and, subsequently, stabilization of p22(phox), a regulatory subunit for NOX1-4...
September 22, 2016: Experimental Hematology
Qian Zhang, Ying Xiong, Guo-Bing Li, Qin Tang, Min Cao, Jing-Bin Huang, Mao Xing, Chang-Peng Hu, Ya Gong, Qing-Hua Wang, Ning Gao, Rong Zhang
ETHNOPHARMACOLOGICAL RELEVANCE: Xinqin, a polyherbal medicine, is an important traditional Chinese herbal formula used in traditional oriental medicine for treatment of allergic rhinitis (AR). The formula is based on the Chinese Pharmacopoeia. AIM OF THE STUDY: Previously, Xinqin exhibited potent anti-allergic effect in a guinea pig model of AR. In this study, we explored the molecular mechanism of the anti-allergic effect mediated by Xinqin. MATERIALS AND METHODS: AR was induced in guinea pigs (Hartley) with toluene-2, 4-diisocyanate (TDI) in vivo and in HMC-1 mast cells with A23187/ phorbol 12-myristate-13-acetate (PMA) in vitro...
September 22, 2016: Journal of Ethnopharmacology
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