Evaluation of Signal Transducer and Activator of Transcription 3 (STAT-3) Protein Expression in Non-Hodgkin Lymphoma Cases in Hospital USM
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Evolving targeted therapy on Janus Associated Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway, especially pertaining to STAT-3 protein in non-Hodgkin lymphoma (NHL), provides new treatment strategies. STAT-3 protein also relates to the prognostication of NHL. Hence, we aimed to evaluate the expression of STAT-3 protein in NHL cases diagnosed in Hospital Universiti Sains Malaysia (USM).A retrospective cross sectional study using formalin fixed paraffin embedded (FFPE) tissue blocks of 95 NHL cases were obtained. STAT-3 immunostaining was performed and evaluated. The proportion and association between the expression of STAT-3 protein with subtypes of NHL were statistically analyzed.The majority of the cases (78.9%) had positive STAT-3 protein expression. 64.2% were among aggressive B cell NHL, whilst 20.0% of them were diffuse large B cell lymphoma, a non-germinal center B subtype (DLBCL-NGCB). There is also an association between STAT-3 protein expression with DLBCL subtypes (p = 0.046).Our study demonstrated a remarkable expression of STAT-3 protein in NHL, in which DLBCL subtypes had significant association. A larger scale study with a combination of JAK protein evaluation should be undertaken in the future.Keywords:
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Abstract The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.
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Tyrosine kinase 2
Janus kinase 1
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Cytokine receptor
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SOCS6
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The janus kinase(JAK) family and the signal transducer and activator of transcription (STAT) family members have been shown to be activated by a number of cytokines, growth factors and oncogenic tyrosine kinases, and called the JAK-STAT pathways collectively. The JAK-STAT families have been shown to play critical roles in determining growth, differentiation and death of normal and transformed cells. The outlines of the recent progresses in the JAK-STAT signaling pathways are presented, including results with gene targeting mice deficient of each JAK and STAT molecule and results with recent reports especially on the synergistic or contradictory roles of STAT3 and Ras/MAP kinase pathways in controlling cell growth and differentiation.
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Signalling
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The signal transducers and activators of transcription (STATs) are a family of transcription factors, which were originally identified on the basis of their ability to transduce a signal from a cellular receptor into the nucleus and modulate the transcription of specific genes. Interestingly, recent studies have demonstrated that STAT-1 plays a key role in promoting apoptosis in a variety of cell types, whereas STAT-3 has an anti-apoptotic effect. Moreover, whilst STAT-3 promotes cellular proliferation and is activated in a variety of tumour cells, STAT-1 appears to have an anti-proliferative effect. Although the initially characterised signal transduction events mediated by STAT-1 and STAT-3 involve the DNA binding and transcriptional activation domains of the factor, some of their other effects appear not to require DNA binding. Therefore, STAT-1 and STAT-3 can mediate the regulation of gene transcription both by direct DNA binding and via a co-activator mechanism and despite their very similar structures, have antagonistic effects on cellular proliferation and apoptosis.
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The interferon-gamma (IFN-γ) signal transduction pathway closely resembles the canonical Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. The IFN-γ Pathway is thus a paradigm for most other JAK-STAT pathways that result in dimerization of STAT transcription factors in response to phosphorylation, including the mammalian STAT4, STAT5A, STAT5B, and STAT6, as well as orthologous systems in various organisms. IFN-γ is a crucial component of innate and adaptive immunity. The Connections Map shows activation of STAT1 by JAK1 and JAK2 and includes several negative regulators of the pathway. Science Viewpoint D. S. Aaronson, C. M. Horvath, A road map for those who don't know JAK-STAT. Science 296 , 1653-1655 (2002). [ Abstract ] [ Full Text ]
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In this study The real-time PCR assays based on TaqMan probes for detection of cytokine Janus Kinase(JAK-1,JAK-2),signal transducers and activators of transcription(STAT-1,STAT-2) were established.Results indicated that the established assays were highly specific and sensitive with a detection limit of 1.0×10 copies/μL,and the coefficient of variation were less than 2 percent for both inter-and intra-assay.The assays were used to detect mRNA of JAK-1,JAK-2,STAT-1,STAT-2 with β-actin mRNA transcription levels in ST cells infected with porcine parvovirus.The results showed the transcription levels of mRNA of JAK-1 and JAK-2 were up-regulated,and others showed down-regulared.The assays with high specificity,sensibility and reproducibility could be used to detect and quantify the signal transduction factors of JAK-STAT pathway.
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Drosophila has been instrumental as a model system in studying signal transduction and revealing molecular functions in development and human diseases. A point mutation in the Drosophila Janus kinase JAK (called hop) causes constitutive activation of the JAK/STAT pathway. We provide robust genetic evidence that the Homeodomain interacting protein kinase (Hipk) is required for endogenous JAK/STAT activity. Overexpression of Hipk can phenocopy the effects of overactive JAK/STAT mutations and lead to melanized tumors, and loss of Hipk can suppress the effects of hyperactive JAK/STAT. Further, the loss of the pathway effector Stat92E can suppress Hipk induced overgrowth. Interaction studies show that Hipk can physically interact with Stat92E and regulate Stat92E subcellular localization. Together our results show that Hipk is a novel factor required for effective JAK/STAT signaling.
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The immune response is regulated by the concerted action of pro- and anti-inflammatory cytokines. The deregulation of this process causes immunological disorders like allergic and autoimmune diseases. The Janus Kinase (JAK) - Signal transducer and activator of transcription (STAT) pathway is one major signaling pathway converting the cytokine signal into gene expression programs regulating the proliferation and differentiation of the immune cells. Several members of the STAT protein family in particular STAT1, STAT2, STAT3, STAT4 and STAT6 act as transcription factors in modulating pro- and anti-inflammatory responses. Here we review the evidence for the involvement of the different STAT proteins in inflammation, autoimmune and allergic diseases. We discuss novel approaches to interfere with the function of these signaling transcription factors for therapeutic purpose. Keywords: inflammation, jak, stat, socs, signaling, pathway, cytokine, autoimmunity
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