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Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
May 22, 2017: Oncotarget
Huading Lu, Lei Zhu, Liyi Lian, Mingwei Chen, Dehai Shi, Kun Wang
Interferon regulatory transcription factor 1 (IRF-1) regulates downstream signals of tumor necrosis factor α (TNF-α). The activity of IRF-1 is mediated by Jak/Stat signaling pathway. In this study, we found that PPAR γ coactivator-1α (PGC-1α) is able to suppress the induction of IRF-1. Treatment with TNF-α in MC3T3 cells leads to a sustainable increase in the expression of IRF-1 and its target gene cyclooxygenase 2 (COX-2). In contrast, TNF-α treatment led to a sustainable reduction in expression of PGC-1α...
April 2015: IUBMB Life
Sahana Holla, Mariola Kurowska-Stolarska, Jagadeesh Bayry, Kithiganahalli Narayanaswamy Balaji
Autophagy is one of the major immune mechanisms engaged to clear intracellular infectious agents. However, several pathogens have evolved strategies to evade autophagy. Here, we demonstrated that Mycobacteria, Shigella, and Listeria but not Klebsiella, Staphylococcus, and Escherichia inhibit IFNG-induced autophagy in macrophages by evoking selective and robust activation of WNT and SHH pathways via MTOR. Utilization of gain- or loss-of-function analyses as well as mir155-null macrophages emphasized the role of MTOR-responsive epigenetic modifications in the induction of Mir155 and Mir31...
February 2014: Autophagy
V Shanker, G Trincucci, H M Heim, H T F Duong
Mammalian cells have developed several mechanisms to sense viruses and initiate adequate responses such as production of interferons. Interferons activate the antiviral response through the Jak-STAT signalling pathway. To establish a chronic infection, viruses need to counteract this barrier of defence. The hepatitis C and hepatitis B viruses are known to up-regulate the expression of protein phosphatase 2A (PP2A). In this study, we show that PP2Ac associates with Jak1/Tyk2/STAT1 and reduces Jak1/Tyk2/STAT1 phosphorylation resulting in an impairment of the IFNα-induced HCV antiviral response...
September 2013: Journal of Viral Hepatitis
Javier Escobar, Javier Pereda, Gerardo López-Rodas, Juan Sastre
Histone acetylation via CBP/p300 coordinates the expression of proinflammatory cytokines in the activation phase of inflammation, particularly through mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB), and signal transducers and activators of transcription (STAT) pathways. In contrast, histone deacetylases (HDACs) and protein phosphatases are mainly involved in the attenuation phase of inflammation. The role of reactive oxygen species (ROS) in the inflammatory cascade is much more important than expected...
March 1, 2012: Free Radical Biology & Medicine
Manisha C Yadav, E M E Burudi, Mehrdad Alirezaei, Claudia C Flynn, Debbie D Watry, Caroline M Lanigan, Howard S Fox
Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-gamma and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-gamma in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia...
October 2007: Glia
Wei Lun Nien, Shauna M Dauphinee, Lori D Moffat, Catherine K L Too
Alpha4 phosphoprotein in the mTOR pathway is a prolactin (PRL)-downregulated gene product that interacts with the catalytic subunit of serine/threonine protein phosphatase 2A (PP2Ac) in rat Nb2 lymphoma cells. Transient overexpression of alpha4 in COS-1 cells inhibited PRL-inducible interferon-regulatory-1 (IRF-1) promoter activity, but the mechanism underlying this inhibition was not known. The present study showed a stable alpha4-PP2Ac complex that was not dissociated by rapamycin in COS-1 cells. Transient overexpression of alpha4 in COS-1 cells had no effect on endogenous PP2Ac protein levels but significantly increased PP2Ac carboxymethylation and PP2A activity as compared to controls...
January 15, 2007: Molecular and Cellular Endocrinology
Guray Saydam, Hikmet Hakan Aydin, Fahri Sahin, Nur Selvi, Gulperi Oktem, Ender Terzioglu, Filiz Buyukkececi, Serdar Bedii Omay
Interferon-alpha (IFN-alpha)-2b is known to have antiproliferative effects on hematological malignant cells, especially chronic myelogenous leukaemia (CML). However, it can induce cytogenetical remissions in a very small percentage of the patients. Also during interferon therapy, resistance can emerge in the CML clones. K562 is an in vitro model cell line transformed from a Ph positive CML patient. It can be induced to differentiate to granulocytic and/or monocytic lineages with certain molecules. IFN-alpha-2b generally exerts its effects on CML cells by Janus family kinases (Jak/Stat) pathway, mostly through tyrosine kinase system...
August 2003: Leukemia Research
Qian Zhang, Puthryaveett N Raghunath, Liquan Xue, Miroslaw Majewski, David F Carpentieri, Niels Odum, Stephan Morris, Tomasz Skorski, Mariusz A Wasik
Accumulating evidence indicates that expression of anaplastic lymphoma kinase (ALK), typically due to t(2;5) translocation, defines a distinct type of T/null-cell lymphoma (TCL). The resulting nucleophosmin (NPM) /ALK chimeric kinase is constitutively active and oncogenic. Downstream effector molecules triggered by NPM/ALK remain, however, largely unidentified. Here we report that NPM/ALK induces continuous activation of STAT3. STAT3 displayed tyrosine phosphorylation and DNA binding in all (four of four) ALK+ TCL cell lines tested...
January 1, 2002: Journal of Immunology: Official Journal of the American Association of Immunologists
A Woetmann, M Nielsen, S T Christensen, J Brockdorff, K Kaltoft, A M Engel, S Skov, C Brender, C Geisler, A Svejgaard, J Rygaard, V Leick, N Odum
Signal transducers and activators of transcription (STATs) are rapidly phosphorylated on tyrosine residues in response to cytokine and growth factor stimulation of cell surface receptors. STATs hereafter are translocated to the nucleus where they act as transcription factors. Recent reports suggest that serine phosphorylation of STATs also is involved in the regulation of STAT-mediated gene transcription. Here, we studied the role of serine/threonine phosphatases in STAT3 signaling in human antigen-specific CD4(+) T cell lines and cutaneous T cell lymphoma lines, expressing a constitutively activated STAT3...
September 14, 1999: Proceedings of the National Academy of Sciences of the United States of America
H Liang, V J Venema, X Wang, H Ju, R C Venema, M B Marrero
Ligand binding to the angiotensin II (Ang II) AT1 receptor on vascular smooth muscle cells (VSMCs) activates the Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. We have shown previously that the JAK2 tyrosine kinase and the Src family p59 Fyn tyrosine kinase are required for Ang II-induced STAT1 tyrosine phosphorylation in VSMCs. The mitogen-activated protein kinase phosphatase, MKP-1, is required for STAT1 tyrosine dephosphorylation. In the present study, using specific enzyme inhibitors and antisense oligonucleotides, we show that Ang II-induced tyrosine phosphorylation and nuclear translocation of STAT3 in VSMCs is mediated by p60 c-Src, whereas tyrosine dephosphorylation is mediated by calcineurin...
July 9, 1999: Journal of Biological Chemistry
J Bardgette, H E Abboud, G G Choudhury
Vanadate is an insulinomimetic agent that has potent inhibitory effect on tyrosine phosphatases. We have recently demonstrated that low concentration of vanadate stimulates phosphotyrosine-dependent signal transduction pathways leading to gene expression and DNA synthesis in mesangial cells. To further examine the mechanisms by which vanadate activates mesangial cell, we studied its effect on signal transducer and activators of transcription (STAT). Incubation of lysates from vanadate-stimulated mesangial cells with a specific high affinity sis-inducible DNA element (SIE) resulted in the formation of protein-DNA complex...
September 1999: Journal of Receptor and Signal Transduction Research
D K Fuhrer, Y C Yang
Interleukin-11 is a stromal derived cytokine important in hematopoiesis. IL-11 intracellular signaling travels through cytoplasmic kinases of the Janus family. How JAKs accomplish the multiple functions of IL-11 has not been determined and until recently only a few associated downstream proteins have been identified. We present evidence here for the IL-11 induced association of PP2A, P13K, and Yes to JAK2. Reciprocal immunoprecipitations support the mutual involvement of these signaling components in IL-11 mediated signal transduction...
July 16, 1996: Biochemical and Biophysical Research Communications
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