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Ebersbach, Celina, Alicia-Marie K. Beier, Christian Thomas, and Holger H. H. Erb. "Impact of STAT Proteins in Tumor Progress and Therapy Resistance in Advanced and Metastasized Prostate Cancer." Cancers 13, no. 19 (September 28, 2021): 4854. http://dx.doi.org/10.3390/cancers13194854.
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Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in several biological processes such as immune response, cell survival, and cell growth. However, they have also been implicated in the development and progression of several cancers, including prostate cancer (PCa). Although the members of the STAT protein family are structurally similar, they convey different functions in PCa. STAT1, STAT3, and STAT5 are associated with therapy resistance. STAT1 and STAT3 are involved in docetaxel resistance, while STAT3 and STAT5 are involved in antiandrogen resistance. Expression of STAT3 and STAT5 is increased in PCa metastases, and together with STAT6, they play a crucial role in PCa metastasis. Further, expression of STAT3, STAT5, and STAT6 was elevated in advanced and high-grade PCa. STAT2 and STAT4 are currently less researched in PCa. Since STATs are widely involved in PCa, they serve as potential therapeutic targets. Several inhibitors interfering with STATs signaling have been tested unsuccessfully in PCa clinical trials. This review focuses on the respective roles of the STAT family members in PCa, especially in metastatic disease and provides an overview of STAT-inhibitors evaluated in clinical trials.
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Konjevic, Gordana. "STAT proteins in cancerogenesis and therapy of malignancies." Srpski arhiv za celokupno lekarstvo 137, no. 1-2 (2009): 98–105. http://dx.doi.org/10.2298/sarh0902098k.
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Signal transducers and activators of transcription (STAT) proteins are a 7-member family of cytoplasmic transcription fators that participate in signal transduction by cytokines, hormones, and growth factors. STAT proteins control the most important cellular processes, including survival, proliferation and differentiation. A great number of cytokines and other factors in different cell types activate STAT1, STAT3 and STAT5 and in this manner regulate processes such as cellular proliferation, differentiation and survival. STATs such as STAT4 and STAT6 have a more specific effect and are engaged in the differentiation of T helper cell populations. Given the critical roles of STAT proteins it has been established in many studies that STAT3 and STAT5 are oncogenes that can contribute to cellular transformation by increasing proliferation and slowing-down apoptosis. On the other hand, STAT1 is a tumour suppressor gene and its inactivation contributes to malignant transformation. Initially STAT proteins were extensively studied in leukaemias, but later their role in the development of different solid tumours has been also shown. Aside from their role in the development of tumours, STAT1, STAT3 and STAT5 can be considered as molecular markers for early detection of certain types of tumours, as well as prognostic factors in the determination of tumour aggressiveness and predictors of response to various types of therapy. Evidence of the deregulation of STAT signalling pathway can serve as a basis for designing novel targeted molecular therapeutic strategies that carry a great potential in the therapy of solid tumours and leukaemias.
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de Haas, Nienke, Coco de Koning, Stefania di Blasio, Georgina Flórez-Grau, I. Jolanda M. de Vries, and Stanleyson V. Hato. "STAT Family Protein Expression and Phosphorylation State during moDC Development Is Altered by Platinum-Based Chemotherapeutics." Journal of Immunology Research 2019 (June 11, 2019): 1–12. http://dx.doi.org/10.1155/2019/7458238.
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The STAT signaling pathway is important in dendritic cell (DC) development and function. Tumor cells can induce STAT signaling, thereby inhibiting DC maturation and immunostimulatory functions, leading to hampered efficacy of DC-based immunotherapies. Platinum-based chemotherapeutics can inhibit STAT signaling, thereby making them an interesting tool to improve DC development and function. In this study, we provide a comprehensive overview of STAT expression and phosphorylation during DC differentiation and maturation and investigate the effects of platinum drugs on STAT signaling during these processes. Monocytes were differentiated into monocyte-derived DCs (moDCs) with IL-4 and GM-CSF and matured with cytokines or TLR ligands. STAT expression and phosphorylation were analyzed by western blotting, and moDC viability and phenotype were analyzed by flow cytometry. Platinum drugs were added at day 3 of differentiation or at the start of maturation to investigate regulation of the STAT signaling pathway. All STAT proteins were expressed during moDC differentiation and STAT1, STAT5, and STAT6 were phosphorylated. No significant changes occurred in the expression and phosphorylation state of the STAT proteins during differentiation. After maturation with TLR ligands, the expression of STAT1 increased, but other STAT proteins were not affected. Phosphorylation of STAT1 and STAT3 increased during maturation, where TLR ligands induced significantly higher levels of phosphorylation than cytokines. Platinum drugs cisplatin and oxaliplatin significantly inhibited phosphorylation of STAT6 during differentiation and maturation. Treatment did not affect the phenotype or viability of the cells. As STAT6 is an important regulator of DC function, these findings suggest a role for platinum-based chemotherapeutics to enhance DC function via inhibition of STAT signaling, thereby potentially enhancing efficacy of DC-based immunotherapies.
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Lee, Hyun-Ku, Gita Singh, and Sujay Singh. "STAT reporter cell line systems as a tool for cancer therapeutic target screening." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 169.8. http://dx.doi.org/10.4049/jimmunol.200.supp.169.8.
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Abstract Signal transducer and activator of transcription (STAT) proteins as cytoplasmic transcription factors respond to cytokines and growth factors that mediate downstream signaling. STATs are closely related with cancers as they are frequently found to be dysregulated in primary tumors, leading to enhanced survival of tumors and increased angiogenesis. Among seven STAT family members, STAT3, STAT4 and STAT5 are considered to primarily promote cancer development and progression, while STAT1 may function either as a tumor suppressor or tumor promoter. STAT3, 4 and 5 are persistently activated in many human cancer cell lines, leading to increased cancer cell survival. Several studies demonstrate that inhibition of STAT3 or STAT5 signaling decreases cancer cell proliferation leading to apoptosis. Taken together, these indicate that STAT proteins can be ideal targets for anti-cancer therapy, and so it is crucial to develop assay systems that can identify inhibitors targeting those pro-tumorigenic STATs. Hence we developed the four reporter cell lines, each of which stably expresses STAT1-, STAT3-, STAT4-, or STAT5-response element that controls an optimized Renilla luciferase reporter gene upon stimulation. Functional activity of each cell line was evaluated through dose response of various cytokines such as IFNs, IL-3 and IL-6. One of the STAT inhibitors, curcumin as well as other putative STAT suppressors were utilized to characterize how each STAT can differentially respond to each test molecule and how its response can affect the host cells.
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Gorissen, Marnix, Erik de Vrieze, Gert Flik, and Mark O. Huising. "STAT genes display differential evolutionary rates that correlate with their roles in the endocrine and immune system." Journal of Endocrinology 209, no. 2 (February 17, 2011): 175–84. http://dx.doi.org/10.1530/joe-11-0033.
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We identified orthologues of all mammalian Janus kinase (JAK) and signal transducer and activator of transcription (STAT) genes in teleostean fishes, indicating that these protein families were already largely complete before the teleost tetrapod split, 450 million years ago. In mammals, the STAT repertoire consists of seven genes (STAT1, -2, -3, -4, -5a, -5b, and -6). Our phylogenetic analyses show that STAT proteins that are recruited downstream of endocrine hormones (STAT3 and STAT5a and -5b) show a markedly higher primary sequence conservation compared with STATs that convey immune signals (STAT1-2, STAT4, and STAT6). A similar dichotomy in evolutionary conservation is observed for the JAK family of protein kinases, which activate STATs. The ligands to activate the JAK/STAT-signalling pathway include hormones and cytokines such as GH, prolactin, interleukin 6 (IL6) and IL12. In this paper, we examine the evolutionary forces that have acted on JAK/STAT signalling in the endocrine and immune systems and discuss the reasons why the JAK/STAT cascade that conveys classical immune signals has diverged much faster compared with endocrine JAK/STAT paralogues.
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Tian, SS, P. Tapley, C. Sincich, RB Stein, J. Rosen, and P. Lamb. "Multiple signaling pathways induced by granulocyte colony-stimulating factor involving activation of JAKs, STAT5, and/or STAT3 are required for regulation of three distinct classes of immediate early genes." Blood 88, no. 12 (December 15, 1996): 4435–44. http://dx.doi.org/10.1182/blood.v88.12.4435.bloodjournal88124435.
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Granulocyte colony-stimulating factor (G-CSF) is the major regulator of proliferation and differentiation of neutrophilic granulocyte precursor cells. G-CSF activates multiple signaling molecules, including the JAK1 and JAK2 kinases and the STAT transcription factors. To investigate G-CSF signaling events regulated by the JAK-STAT pathway, we have generated UT7-epo cells stably expressing either wild-type (wt) G-CSF receptor or a series of C-terminal deletion mutants. Gel mobility shift and immunoprecipitation/Western analysis showed that STAT5 is rapidly activated by G-CSF in cells expressing the wt G-CSF receptor, in addition to the previously reported STAT3 and STAT1. Mutants lacking any tyrosine residues in the cytoplasmic domain maintain their ability to activate STAT5 and STAT1 but cannot activate STAT3, implying that STAT5 and STAT1 activation does not require receptor tyrosine phosphorylation. We also observed significant changes in the ratio of STAT1:STAT3:STAT5 activated by various G-CSF receptor C-terminal deletion mutants. These mutant receptors were further used to investigate the role of JAKs and STATs in G-CSF-mediated responses in these cells. We found that JAK activation correlates with G-CSF-induced cell proliferation, whereas STAT activation is not required. We have also identified three classes of G-CSF immediate early genes, whose activation correlates with the activation of distinct JAK-STAT pathways. Our data show that, whereas c-fos is regulated through a pathway independent of STAT activation, oncostatin M, IRF-1, and egr-1 are regulated by an STAT5-dependent pathway and fibrinogen is regulated by an STAT3-dependent pathway. In conclusion, our results suggest that G-CSF regulates its complex biologic activities by selectively activating distinct early response genes through different JAK-STAT signaling molecules.
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Chen, Honglin, Lindsey Hutt-Fletcher, Liang Cao, and S. Diane Hayward. "A Positive Autoregulatory Loop of LMP1 Expression and STAT Activation in Epithelial Cells Latently Infected with Epstein-Barr Virus." Journal of Virology 77, no. 7 (April 1, 2003): 4139–48. http://dx.doi.org/10.1128/jvi.77.7.4139-4148.2003.
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ABSTRACT STAT3 and STAT5 are constitutively activated and nuclear in nasopharyngeal carcinoma (NPC) cells. In normal signaling, STATs are only transiently activated. To investigate whether Epstein-Barr virus (EBV), and in particular the protein LMP1, contributes to sustained STAT phosphorylation and activation in epithelial cells, we examined STAT activity in two sets of paired cell lines, HeLa, an EBV-converted HeLa cell line, HeLa-Bx1, the NPC-derived cell line CNE2-LNSX, and an LMP1-expressing derivative, CNE2-LMP1. EBV infection was associated with a significant increase in the tyrosine-phosphorylated forms of STAT3 and STAT5 in HeLa-Bx1 cells. This effect correlated with LMP1 expression, since phosphorylated STAT3 and STAT5 levels were also increased in CNE2-LMP1 cells relative to the control CNE2-LNSX cells. No change was observed in STAT1 or STAT6 phosphorylation in these cell lines, nor was there a significant change in the levels of total STAT3, STAT5, STAT1, or STAT6 protein. Tyrosine phosphorylation allows the normally cytoplasmic STAT proteins to enter the nucleus and bind to their recognition sequences in responsive promoters. The ability of LMP1 to activate STAT3 was further established by immunofluorescence assays in which coexpression of LMP1 in transfected cells was sufficient to mediate nuclear relocalization of Flag-STAT3 and by an electrophoretic mobility shift assay which showed that LMP1 expression in CNE2-LNSX cells was associated with increased endogenous STAT3 DNA binding activity. In addition, the activity of a downstream target of STAT3, c-Myc, was upregulated in HeLa-Bx1 and CNE2-LMP1 cells. A linkage was established between interleukin-6 (IL-6)- and LMP1-mediated STAT3 activation. Treatment with IL-6 increased phosphorylated STAT3 levels in CNE2-LNSX cells, and conversely, treatment of CNE2-LMP1 cells with IL-6 neutralizing antibody ablated STAT3 activation and c-Myc upregulation. The previous observation that STAT3 activated the LMP1 terminal repeat promoter in reporter assays was extended to show upregulated expression of endogenous LMP1 mRNA and protein in HeLa-Bx1 cells transfected with a constitutively activated STAT3. A model is proposed in which EBV infection of an epithelial cell containing activated STATs would permit LMP1 expression. This in turn would establish a positive feedback loop of IL-6-induced STAT activation, LMP1 and Qp-EBNA1 expression, and viral genome persistence.
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Murphy, Theresa L., Erik D. Geissal, J. David Farrar, and Kenneth M. Murphy. "Role of the Stat4 N Domain in Receptor Proximal Tyrosine Phosphorylation." Molecular and Cellular Biology 20, no. 19 (October 1, 2000): 7121–31. http://dx.doi.org/10.1128/mcb.20.19.7121-7131.2000.
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ABSTRACT Stat4 is activated by the cytokines interleukin 12 and alpha interferon (IFN-α) and plays a significant role in directing development of naı̈ve CD4+ T cells to the Th1 phenotype. Signal transducers and activators of transcription (STAT) proteins undergo phosphorylation on a conserved tyrosine residue, resulting in homo- and heterodimerization, nuclear translocation, and DNA binding. Stat4 can bind to single IFN-γ-activated sites (GASs) as a dimer or bind two tandem GASs as a pair of STAT dimers, or tetramer, stabilized through N-terminal domain (N domain) interactions between dimers. We uncovered an unexpected effect of the Stat4 N domain in controlling the proximal activation of Stat4 by tyrosine phosphorylation at activated receptor complexes. Mutation of the N domain at tryptophan residue W37, predicted to interrupt N domain dimer formation, unexpectedly prevented IFN-α-induced tyrosine phosphorylation of the Stat4 monomer, blocking dimer formation and nuclear translocation. Furthermore, N domains appear to exert private STAT functions, since interchanging the N domains between Stat1 and Stat4 prevented receptor-mediated tyrosine phosphorylation in one case and interrupted STAT-specific gene activation in another. Finally, replacement of the N domain of Stat1 with that of Stat4 abrogated the normal Stat2 dependence of Stat1 phosphorylation, again suggesting the domains are not equivalent. Thus, in addition to its role in STAT tetramerization, the conserved STAT N domain appears to participate in very proximal steps of receptor-mediated ligand-induced tyrosine phosphorylation.
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Guo, DanQun, James D. Dunbar, Chuan He Yang, Lawrence M. Pfeffer, and David B. Donner. "Induction of Jak/STAT Signaling by Activation of the Type 1 TNF Receptor." Journal of Immunology 160, no. 6 (March 15, 1998): 2742–50. http://dx.doi.org/10.4049/jimmunol.160.6.2742.
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Abstract Cellular responses to TNF are initiated by either of two cell surface receptors, the type 1 TNF receptor (TNFR1) and the type 2 TNF receptor (TNFR2). Although neither receptor contains an intrinsic protein tyrosine kinase, such activity has been implicated in TNF action. In this study, we show that murine TNF induces the tyrosine phosphorylation and activation of the intracellular Janus tyrosine kinases Jak1, Jak2, and Tyk2 in murine 3T3-L1 adipocytes. Activation of Jak kinases by TNF was associated with tyrosine phosphorylation of STAT1, STAT3, STAT5, and STAT6, but not STAT2 or STAT4, showing that TNF acts on a specific subset of these latent cytoplasmic transcription factors in 3T3-L1 adipocytes. Agonist antiserum to TNFR1 induced Jak kinase and STAT protein phosphorylation. Phosphorylation of Jak proteins was also induced by human TNF, which selectively binds to TNFR1 on murine cells. 35S-labeled Jak kinases were precipitated from a cell-free system and from lysates of 3T3-L1 adipocytes by a glutathione S-transferase fusion protein containing the cytoplasmic domain of TNFR1. These results suggest that the cytoplasmic domain of TNFR1 can directly interact with and form signaling complexes with Jak kinases. Jak2 was precipitated from HeLa cells by antiserum to TNFR1, directly demonstrating their association in vivo. Thus, TNF activates a Jak/STAT signal-transduction cascade by acting through TNFR1.
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Morgan, Ethan L., and Andrew Macdonald. "Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies." Viruses 12, no. 9 (September 3, 2020): 977. http://dx.doi.org/10.3390/v12090977.
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Human papillomaviruses (HPVs) are small, DNA viruses that cause around 5% of all cancers in humans, including almost all cervical cancer cases and a significant proportion of anogenital and oral cancers. The HPV oncoproteins E5, E6 and E7 manipulate cellular signalling pathways to evade the immune response and promote virus persistence. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has emerged as a key mediator in a wide range of important biological signalling pathways, including cell proliferation, cell survival and the immune response. While STAT1 and STAT2 primarily drive immune signalling initiated by interferons, STAT3 and STAT5 have widely been linked to the survival and proliferative potential of a number of cancers. As such, the inhibition of STAT3 and STAT5 may offer a therapeutic benefit in HPV-associated cancers. In this review, we will discuss how HPV manipulates JAK/STAT signalling to evade the immune system and promote cell proliferation, enabling viral persistence and driving cancer development. We also discuss approaches to inhibit the JAK/STAT pathway and how these could potentially be used in the treatment of HPV-associated disease.
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Mirza, Noweeda, Soraya Zorro Manrique, Skylar Cohen, Ana Dominguez, Peter Cohen, and Sandra Gendler. "Aging subverts immune function by dictating alternative STAT responses to cytokine signaling (P5078)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 180.22. http://dx.doi.org/10.4049/jimmunol.190.supp.180.22.
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Abstract Chronic inflammation in the aged closely resembles tumor-induced immune suppression, manifested as a progressive T1→T2 shift and an increased presence of MDSCs. We hypothesize that reversing these age-related phenomena should reduce the elderly’s heightened susceptibility to malignancy. We have now optimized real-time analyses of phosphorylated STATs in murine T cells and MDSCs in order to correlate STAT activation with immune suppression. Both young and old T cells responded to IL-4 stimulation with STAT6 activation and to IFN-γ stimulation with STAT1 activation. Uniquely, however, young T cells also phosphorylated STAT1, STAT3 and STAT5 in response to IL-4, and responded to IL-6 with STAT3 activation, all consistent with a greater susceptibility to T1/T17 differentiation. Regarding MDSCs, both old and young displayed constitutive STAT3 activation which could be enhanced by G-CSF or IL-6 treatment. Both young and old MDSCs activated STAT1 briskly in response to IFN-γ, STAT5 in response to GM-CSF and STAT6 in response to IL-4. However, younger MDSCs, like younger T cells, displayed more diverse responsiveness to IL-4, activating not only STAT6 but also STAT1 and STAT3. While chronic in vivo exposure to T2 cytokines may explain the decreased responsiveness of older MDSCs and T cells to IL-4, paradoxically IL-4 still robustly activated STAT6 in these cells. Such selective responsiveness may be required to preserve the immune suppressive potential of older MDSCs.
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Miyakawa, Y., A. Oda, BJ Druker, H. Miyazaki, M. Handa, H. Ohashi, and Y. Ikeda. "Thrombopoietin induces tyrosine phosphorylation of Stat3 and Stat5 in human blood platelets." Blood 87, no. 2 (January 15, 1996): 439–46. http://dx.doi.org/10.1182/blood.v87.2.439.bloodjournal872439.
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Thrombopoietin is known to be essential for megakaryocytopoiesis and thrombopoiesis. Recently, we and others have shown that thrombopoietin induces rapid tyrosine phosphorylation of Jak2 and other proteins in human platelets and BaF3 cells, genetically engineered to express c- Mpl, a receptor for thrombopoietin. The Jak family of tyrosine kinases are known to mediate some of the effects of cytokines or hematopoietic growth factors by recruitment and tyrosine phosphorylation of a variety of Stat (signal transducers and activators of transcription) proteins. Hence, we have investigated whether Stat proteins are present in platelets and, if so, whether they become tyrosine phosphorylated in response to thrombopoietin. We immunologically identified Stat1, Stat2, Stat3, and Stat5 in human platelet lysates. Thrombopoietin induced tyrosine phosphorylation of Stat3 and Stat5 in these cells. Thrombopoietin also induced tyrosine phosphorylation of Stat3 and Stat5 in FDCP-2 cells genetically engineered to constitutively express human c-Mpl. Thus, our data indicate that Stat3 and Stat5 may be involved in signal transduction after ligand binding to c-Mpl and that this event may have a role in megakaryopoiesis/thrombopoiesis or possibly a mature platelet function such as aggregation.
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Demirci Yildirim, T., A. Kahraman Akkalp, A. Köken Avşar, F. Onen, S. Akar, and İ. Sari. "AB1480 EXPRESSION OF JAK-STAT SIGNALING PATHWAY IN HIDRADENITIS SUPPURATIVA PATHOLOGICAL BIOPSY SPECIMENS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 1969.2–1969. http://dx.doi.org/10.1136/annrheumdis-2023-eular.993.
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BackgroundHidradenitis suppurativa (HS) is inflammatory skin disease with an unknown etiology. JAK-STAT pathway may be implicated in its pathogenesis. Considering the unmet need in the treatment of inflammatory skin diseases, assessment of the JAK/STAT pathway could provide new understanding in the pathogenesis of these disorders. Therefore, in this study we primarily intended to investigate this pathway in patients with HS.ObjectivesHerein we aimed to investigate the JAK/STAT signaling pathway in the skin biopsies of HS patients and compared with psoriasis (PSO) and healthy subject.MethodsThis study used human tissues of healthy (n=26) and diseased skin samples obtained from the psoriatic (n=35) and HS (n=25) patients. Immunohistochemical methods were used to evaluate the expression of JAK1, JAK2, JAK3, Tyrosine Kinase 2 (TYK2), STAT1, STAT3, STAT4, STAT5, and STAT6. In the dermis, the staining intensity was recorded as ‘positive’ or ‘negative. The epidermal part is divided into cytoplasmatic and nuclear parts and strong staining intensity recorded by staining in ≥50% of the cells.ResultsA total of 86 biopsies obtained from 25 HS (40.8 ±21.8 years, 60% male (M)), 35 PSO (46.5 ± 18.4 years, 57% M) and 26 control subjects (60.3 ± 18.3 years, 46% M) were analyzed. All JAK-STAT and TYK2 are overexpressed in dermal part of HS skin. TYK2, JAK3,STAT3 and STAT4 are strongly expressed in cytoplasmic part of epidermis in HS skin.TYK2, JAK3 and STAT1 is strongly expressed in nuclear part of epidermis in HS skin. JAK-STAT pathway is overexpressed in dermal part of psoriatic skin especially STAT2 and STAT6 but JAK1 is not expressed dermal part of psoriatic skin. All STATs and JAK1, JAK3 and TYK2 are strongly expressed in cytoplasmic part of epidermis in psoriatic skin. TYK2, JAK3 and STAT1 are strongly expressed in nuclear part of epidermis in psoriatic skin. The summary of the findings is given in Table 1. When look at the correlation analysis for TYK2 had strong correlation with HS according to control subjects in the dermal and nuclear staining. The summary of findings and the correlation analysis for HS, healty control (HC) and PSO is given in Table 1.ConclusionIn this study, we demonstrated an increased activity in the skin biopsies of HS. When considering the unmet need in the treatment of this disease current data is significant for guiding the possible future therapies.Reference[1] Frew JW, Hawkes JE, Krueger JG. A systematic review and critical evaluation of inflammatory cytokine associations in hidradenitis suppurativa. F1000Research [Internet]. 2018 [cited 2022 Mar 25];7. Available from:/pmc/articles/PMC6392156/Table-1.Summary of the findings and the correlation between inflammatory skin diseases and JAK/STAT pathway staining in the skinHidradenitis Suppurativa (n=25)Psoriasis (n=35)Healthy skin (n=26)HS vs. HC*PSO vs. HS*Dermal stainingTYK223, (92)34, (97.1)00.92JAK13, (8.6)00JAK214, (56)21, (60)2, (7.7)0.52JAK323, (92)31, (88.6)00.92STAT116, (64)27, (77.1)00.69STAT225, (100)35, (100)14, (53.8)0.42STAT323, (92)34, (97.1)00.92STAT44, (16)11, (31.4)00.29STAT517, (68)27, (77.1)00.72STAT614, (56)33, (94.3)00.62-0.45Epidermal cytoplasmic staining in ≥50% of the cellsTYK22, (8)21, (60)8, (30.8)-0.69-0.58JAK18, (32)11, (31.4)0JAK325, (100)35, (100)26, (100)0.44STAT322, (88)34, (97.1)14, (53.8)0.37STAT415, (60)29, (82.9)14, (53.8)-0.25Epidermal nuclear cells with strong stainingTYK25, (20)27, (77.1)00.76-0.56JAK325, (100)35, (100)26, (100)STAT119, (76)31, (88.6)19, (73.1)* Note that “r” correlation coefficients were given in the cells which indicated significant correlations between the variables (p<0.05). Empty cells indicated no correlation (p>0.05) therefore “r” values were not provided.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Jones, Dan, Justin Windham, Brian Stewart, Luis Fayad, Alma Rodriguez, and Fredrick B. Hagemeister. "Differential JAK-STAT Pathway Activation in Primary Mediastinal Large B-Cell Lymphoma: Two Subgroups with Differential Cytokine Activation Patterns and Predicted Responses to Kinase Inhibitors." Blood 114, no. 22 (November 20, 2009): 968. http://dx.doi.org/10.1182/blood.v114.22.968.968.
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Abstract Abstract 968 Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a specialized type of diffuse large B-cell lymphoma which shows diagnostic and pathogenetic overlap with mediastinal classical Hodgkin lymphoma. Approximately 60% of patients with PMBCL have good response to conventional chemoradiotherapy with the rest often showing distant relapses. Microarray studies of PMBCL have revealed overexpression of components and targets of the JAK-STAT signaling pathways including upregulation of IL13 receptor and STAT1; a subset of PMBCL have genome amplification of JAK2 or deletion of the JAK suppressor SOCS1. Given this complexity, we examined the most common mechanism and effects of JAK-STAT dysregulation in a series of newly diagnosed and recurrent PMBCL. Methods: Fifty-three biopsies from 23 patients with PMBCL were assessed and correlated with outcome. JAK2 and SOCS1 copy number status were determined by quantitative PCR on genomic DNA. JAK-STAT pathway activation was probed using reverse transcription quantitative (RQ)-PCR for JAK2, JAK3, and a panel of IL-4 and IL-13 transcriptional targets. JAK-STAT activation was assessed in tissue arrays using antisera against phospho-activation epitopes of STAT1, STAT3, STAT5, and STAT6 using immunohistochemistry (IHC). Activation patterns were modeled in the PMBCL cell line Karpas (K)1106P at baseline and following IL-4 and IL-13 stimulation with or without a range of small molecule inhibitors and blocking antibodies. Growth parameters were measured by MTT and protein levels by flow cytometry, Western blot, RQ-PCR and kinase profiling. Results: JAK2 genomic amplification was present in 40% of PMBCL and SOCS1 deletion in 10% as well as in the K1106P line. By phospho-activation IHC, tumors in 20/23 (87%) patients showed STAT activation, mostly due to STAT1 (60.8%) followed by STAT3 (26.1%), with 6 cases showing mixed patterns. In different tumors, localized and uniform STAT activation patterns were seen. Constitutive STAT activation was correlated with high expression of IL-4 transcription targets including CCL17 and IL13RA as well as JAK2 autophosphorylation and inferior outcome (p = .007). Tumors with more localized foci of activation were associated with alternate transcription patterns. In the K1106P cell line, IL-4 but not IL-13 treatment led to inducible STAT1 activation whereas baseline STAT3/6 activation was highly regulated by cytokine exposure. The JAK2 inhibitor JSI124 blocked IL-4 induced STAT1 activation whereas the JAK inhibitors AG-490, NSC7908 and WHI-P154 did not but did block IL-4/IL-13-induced STAT3 activation. The JAK3 inhibitor ZM39923 was most effective in blocking cell growth but did not block STAT1 activation. Conclusions: JAK2-STAT pathway activation characterizes nearly all cases of PMBCL but genetic mechanisms are distinct leading to distinct patterns of STAT1 activation (driven predominantly through the type I IL-4 receptor) and STAT3/6 activation (driven predominantly through the type II IL13RA/IL4RA) with differential effects on growth parameters and gene regulation. The patterns of STAT activation and target gene expression in primary tumors comprising these two groups mirrored the response to small molecule inhibitors following cytokine exposure in vitro in the K1106P line and highlights differences between IL-4 and IL-13 signaling in PMBCL. Profiling of PMBCL biopsies with phosphoactivation IHC for STAT isoforms may be useful to subcategorize cases and select the optimal JAK-STAT pathway inhibitors for adjuvant therapy. Disclosures: No relevant conflicts of interest to declare.
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Alunno, Alessia, Ivan Padjen, Antonis Fanouriakis, and Dimitrios T. Boumpas. "Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent." Cells 8, no. 8 (August 15, 2019): 898. http://dx.doi.org/10.3390/cells8080898.
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Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal transducers and activators of transcription (STATs) (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal transduction of more than 50 cytokines and growth factors in many different cell types. Located intracellularly and downstream of cytokine receptors, JAKs integrate and balance the actions of various signaling pathways. With distinct panels of STAT-sensitive genes in different tissues, this highly heterogeneous system has broad in vivo functions playing a crucial role in the immune system. Thus, the JAK/STAT pathway is critical for resisting infection, maintaining immune tolerance, and enforcing barrier functions and immune surveillance against cancer. Breakdowns of this system and/or increased signal transduction may lead to autoimmunity and other diseases. Accordingly, the recent development and approval of the first small synthetic molecules targeting JAK molecules have opened new therapeutic avenues of potentially broad therapeutic relevance. Extensive data are now available regarding the JAK/STAT pathway in rheumatoid arthritis. Dysregulation of the cytokines is also a hallmark of systemic lupus erythematosus (SLE), and targeting the JAK/STAT proteins allows simultaneous suppression of multiple cytokines. Evidence from in vitro studies and animal models supports a pivotal role also in the pathogenesis of cutaneous lupus and SLE. This has important therapeutic implications, given the current paucity of targeted therapies especially in the latter. Herein, we summarize the currently available literature in experimental SLE, which has led to the recent promising Phase II clinical trial of a JAK inhibitor.
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Roby, Justin Alexander, Brian C. Keller, Hilario J. Ramos, Michael S. Diamond, and Michael J. Gale. "The JAK/STAT signaling cascades of multiple cytokines are dysregulated during West Nile virus infection." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 217.38. http://dx.doi.org/10.4049/jimmunol.196.supp.217.38.
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Abstract The neurotropic arthropod-borne flavivirus West Nile virus (WNV) is responsible for sporadic outbreaks of fever and encephalitis in infected humans, with an almost global distribution of circulating strains. During WNV infection in mammals Interferon-α/β (IFN-α/β) drives signaling through JAK/STAT pathways to enhance the expression of antiviral genes with an overall protective effect against WNV infection. However, WNV strains have been demonstrated to be able to antagonize IFN-α/β signaling within infected cells, interrupting this JAK/STAT cascade and promoting viral replication. We hypothesized that JAK/STAT signaling downstream of multiple cytokines would be broadly inhibited in WNV infected cells as a consequence of viral replication. To assess the degree of cytokine signaling in infected cells, A549 and PMA-differentiated THP-1 cells were infected with WNV for 24 hr prior to acute course treatment with various cytokines. We reveal that STAT3 and STAT5 phosphorylation, in addition to STAT1 and STAT2, is blocked in WNV-infected cells in response to IFN-β. Remarkably, JAK/STAT signaling cascades downstream of IFN-γ, IFN-λ3, IL-4, and IL-6 are also similarly dysregulated upon WNV infection, suggesting that global JAK/STAT signaling may be inhibited independent of the identity of the cytokine receptor. The breadth and mechanisms of the WNV-imposed JAK/STAT signaling blockade will be presented.
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Gupta, Sanjay, Man Jiang, and Alessandra B. Pernis. "IFN-α Activates Stat6 and Leads to the Formation of Stat2:Stat6 Complexes in B Cells." Journal of Immunology 163, no. 7 (October 1, 1999): 3834–41. http://dx.doi.org/10.4049/jimmunol.163.7.3834.
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Abstract IFN-α consists of a family of highly homologous proteins, which exert pleiotropic effects on a wide variety of cell types. The biologic activities of IFN-α are mediated by its binding to a multicomponent receptor complex resulting in the activation of the Janus kinase-STAT signaling pathway. In most cell types, activation of Stat1 and Stat2 by IFN-α leads to the formation of either STAT homo-/heterodimers or of the IFN-stimulated gene factor 3 complex composed of Stat1, Stat2, and p48, a non-STAT protein. These distinct transcriptional complexes then target two different sets of cis-elements, γ-activated sites and IFN-stimulated response elements. Here, we report that IFN-α can activate complexes containing Stat6, which, until now, has been primarily associated with signaling by two cytokines with biologic overlap, IL-4 and IL-13. Induction of Stat6 complexes by IFN-α appears to be cell type specific, given that tyrosine phosphorylation of Stat6 in response to IFN-α is predominantly detected in B cells. Activation of Stat6 by IFN-α in B cells is accompanied by the formation of novel Stat2:Stat6 complexes, including an IFN-stimulated gene factor 3-like complex containing Stat2, Stat6, and p48. B cell lines resistant to the antiproliferative effects of IFN-α display a decrease in the IFN-α-mediated activation of Stat6. Activation of Stat6 as well as of Stat2:Stat6 complexes by IFN-α in B cells may allow modulation of target genes in a cell type-specific manner.
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Kirito, Keita, Koichi Nakajima, Tomoko Watanabe, Mie Uchida, Masaru Tanaka, Keiya Ozawa, and Norio Komatsu. "Identification of the human erythropoietin receptor region required for Stat1 and Stat3 activation." Blood 99, no. 1 (January 1, 2002): 102–10. http://dx.doi.org/10.1182/blood.v99.1.102.
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Signal transducers and activators of transcription (Stat) proteins play important roles in the regulation of hematopoiesis as downstream molecules of cytokine signal transduction. It was previously demonstrated that erythropoietin (EPO), a major regulator of erythropoiesis, activates 3 different Stat members, Stat1, Stat3, and Stat5, in a human EPO-dependent cell line, UT-7/EPO. To clarify the mechanism by which EPO activates Stat1 and Stat3 via the EPO receptor (EPOR), a series of chimeric receptors was constructed bearing the extracellular domain of the granulocyte colony-stimulating factor receptor linked to the transmembrane domain of EPOR and the full length or several mutants of the cytoplasmic domain of EPOR, and these chimeric receptor complementary DNAs were introduced into UT-7/EPO cells. Tyr432 on human EPOR was important for activation of Stat1 and Stat3 and c-myc gene induction. In addition, Jak2 and Fes tyrosine kinases were involved in EPO-induced activation of Stat1 and Stat3. These results indicate that Stat1 and Stat3 are activated by EPO via distinct mechanisms from Stat5.
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Mukaddam, Khaled, Sabrina Ruggiero, Steffen M. Berger, Dietmar Cholewa, Sebastian Kühl, Daniel Vegh, Michael Payer, Michael M. Bornstein, Farah Alhawasli, and Elizaveta Fasler-Kan. "Cytokines Activate JAK–STAT Signaling Pathway in MG-63 Cells on Titanium and Zirconia." Materials 15, no. 16 (August 16, 2022): 5621. http://dx.doi.org/10.3390/ma15165621.
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Although titanium has been traditionally used as the gold standard for dental implants, recent years have seen the widespread application of zirconia implants given their superiority with regards to reduced bacterial adhesion, inflammation and cellular-interaction in terms of bio-compatibility. The JAK–STAT signaling pathway plays an important role in bone remodeling and formation. The aim of the study was to investigate the activation of the JAK–STAT pathway through different cytokines in osteoblast-like cells (MG-63) on zirconia in comparison to titanium discs. IFN-γ induced the very strong activation of STAT1 protein, IFN-α activated both STAT1 and STAT3 molecules, IL-6 activated STAT3 and IL-4 induced the activation of STAT6 on both surfaces. The activation of STAT proteins was confirmed by western blot, immunofluorescence and flow cytometry using phospho-specific anti-STAT antibodies, which recognize only phosphorylated STAT proteins. The incubation of MG-63 cells with IFN-γ caused the upregulation of MHC class I and class II proteins when MG-63 cells were grown on zirconia and titanium discs. In sum, the present study shows that the JAK–STAT pathway is activated in MG-63 cells when they are incubated on titanium or zirconia surfaces.
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Ociepa, Kamila, Marian Danilewicz, Małgorzata Wągrowska-Danilewicz, Róża Peterson-Jęckowska, Angelika Wójcicka-Rubin, Natalia Lewkowicz, Radosław Zajdel, and Agnieszka Żebrowska. "Expression of the Selected Proteins of JAK/STAT Signaling Pathway in Diseases with Oral Mucosa Involvement." International Journal of Molecular Sciences 24, no. 1 (December 24, 2022): 323. http://dx.doi.org/10.3390/ijms24010323.
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Background: The JAK/STAT signal pathway is a system of intracellular proteins used by many cytokines and growth factors to express genes responsible for the process of cell activation, proliferation and differentiation. There has been numerous inflammatory and autoimmune diseases identified where the JAK/STAT signaling is disrupted; however, there are only a few papers concerning autoimmune bullous diseases published. The aim of this study was to evaluate the expression of proteins: JAK3, STAT2, STAT4 and STAT6 in epithelium lesions in patients with pemphigus vulgaris (PV), bullous pemphigoid (BP), oral lichen planus (LP) and chronic ulcerative stomatitis (CUS), as well as in the control group. Methods: Immunohistochemistry and immunoblotting were used to evaluate expression of selected proteins. Results: We found significantly higher expression of selected JAK/STAT proteins in oral mucosa lesions in study groups in comparison to the control group, which indicates participation of JAK/STAT pathway in pathogenesis of these diseases. In BP and PV there were no increased STAT2 expression, whereas in CUS and LP no increased STAT4 expression occurred. Conclusions: The differences in expression of JAK/STAT proteins in selected disorders have been observed. These results create new potential therapeutic targets for the treatment.
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Saharinen, Pipsa, Niklas Ekman, Krista Sarvas, Peter Parker, Kari Alitalo, and Olli Silvennoinen. "The Bmx Tyrosine Kinase Induces Activation of the Stat Signaling Pathway, Which Is Specifically Inhibited by Protein Kinase Cδ." Blood 90, no. 11 (December 1, 1997): 4341–53. http://dx.doi.org/10.1182/blood.v90.11.4341.
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Abstract Members of the hematopoietically expressed Tec tyrosine kinase family have an important role in hematopoietic signal transduction, as exemplified by the crucial role of Btk for B-cell differentiation and activation. Although a variety of cell surface receptors have been found to activate Tec tyrosine kinases, the specific signaling pathways and substrate molecules used by Tec kinases are still largely unknown. In this study a Tec family kinase, Bmx, was found to induce activation of the Stat signaling pathway. Bmx induced the tyrosine phosphorylation and DNA binding activity of all the Stat factors tested, including Stat1, Stat3, and Stat5, both in mammalian and insect cells. Bmx also induced transcriptional activation of Stat1- and Stat5-dependent reporter genes. Other cytoplasmic tyrosine kinases, Syk, Fyn, and c-Src, showed no or only weak ability to activate Stat proteins. Expression of Bmx in mammalian cells was found to induce activation of endogenous Stat proteins without activation of endogenous Jak kinases. We further analyzed the Bmx-mediated activation of Stat1, which was found to be regulated by protein kinase C δ (PKCδ) isoform, but not β 1, ε, or ζ isoforms, leading to inhibition of Stat1 tyrosine phosphorylation. In conclusion, these studies show that Bmx, a Tec family kinase, can function as an activator of the Stat signaling pathway and identify a role for PKCδ in the regulation of Bmx signaling.
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Saharinen, Pipsa, Niklas Ekman, Krista Sarvas, Peter Parker, Kari Alitalo, and Olli Silvennoinen. "The Bmx Tyrosine Kinase Induces Activation of the Stat Signaling Pathway, Which Is Specifically Inhibited by Protein Kinase Cδ." Blood 90, no. 11 (December 1, 1997): 4341–53. http://dx.doi.org/10.1182/blood.v90.11.4341.4341_4341_4353.
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Members of the hematopoietically expressed Tec tyrosine kinase family have an important role in hematopoietic signal transduction, as exemplified by the crucial role of Btk for B-cell differentiation and activation. Although a variety of cell surface receptors have been found to activate Tec tyrosine kinases, the specific signaling pathways and substrate molecules used by Tec kinases are still largely unknown. In this study a Tec family kinase, Bmx, was found to induce activation of the Stat signaling pathway. Bmx induced the tyrosine phosphorylation and DNA binding activity of all the Stat factors tested, including Stat1, Stat3, and Stat5, both in mammalian and insect cells. Bmx also induced transcriptional activation of Stat1- and Stat5-dependent reporter genes. Other cytoplasmic tyrosine kinases, Syk, Fyn, and c-Src, showed no or only weak ability to activate Stat proteins. Expression of Bmx in mammalian cells was found to induce activation of endogenous Stat proteins without activation of endogenous Jak kinases. We further analyzed the Bmx-mediated activation of Stat1, which was found to be regulated by protein kinase C δ (PKCδ) isoform, but not β 1, ε, or ζ isoforms, leading to inhibition of Stat1 tyrosine phosphorylation. In conclusion, these studies show that Bmx, a Tec family kinase, can function as an activator of the Stat signaling pathway and identify a role for PKCδ in the regulation of Bmx signaling.
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Palmroth, M., K. Kuuliala, R. Peltomaa, A. Virtanen, A. Kuuliala, A. Kurttila, A. Kinnunen, M. Leirisalo-Repo, O. Silvennoinen, and P. Isomäki. "AB0250 TOFACITINIB SUPPRESSES SEVERAL JAK-STAT PATHWAYS IN RHEUMATOID ARTHRITIS AND BASELINE SIGNALING PROFILE ASSOCIATES WITH TREATMENT RESPONSE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1150.2–1151. http://dx.doi.org/10.1136/annrheumdis-2021-eular.448.
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Background:Cytokines are important mediators of inflammation and tissue destruction in rheumatoid arthritis (RA) 1. Several cytokines involved in RA pathogenesis act through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway 2. The effects of JAK-inhibitor tofacitinib on cytokine signaling in vitro are well established, while in vivo evidence in patients remains scarce.Objectives:To investigate in vivo in rheumatoid arthritis patients i) which JAK-STAT pathways are inhibited by tofacitinib and ii) if baseline signaling profile is associated with the treatment response.Methods:Sixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of basal and cytokine-induced phosphorylated STATs and total STAT1 and STAT3 in peripheral blood monocytes, T cells and B cells were measured by flow cytometry. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response (the change from baseline in disease activity score (DAS28)) was studied by calculating correlation coefficients.Results:Treatment with tofacitinib and csDMARDs decreased median DAS28 from 4.4 to 2.6 (p < 0.001). Tofacitinib significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. Basal STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was downregulated by tofacitinib. No changes were observed in STAT1 and STAT3 protein levels, while gene expression of STAT3, STAT4, STAT5A, JAK1, JAK3 and all studied SOCSs was significantly suppressed. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.Conclusion:Tofacitinib suppresses multiple JAK-STAT pathways in RA patients in vivo. Baseline JAK-STAT signaling profile may be applicable as a prognostic marker for treatment response to tofacitinib.References:[1]McInnes, I. B., Buckley, C. D. & Isaacs, J. D. Cytokines in rheumatoid arthritis-shaping the immunological landscape. Nature Reviews Rheumatology vol. 12 63–68 (2016).[2]Schwartz, D. M., Bonelli, M., Gadina, M. & O’Shea, J. J. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol.12, 25–36 (2016).Acknowledgements:This study was supported by Pfizer Inc.Disclosure of Interests:Maaria Palmroth Consultant of: Pfizer and from 1/21 a part-time employee of MedEngine and consultant for Pfizer, Krista Kuuliala Grant/research support from: Pfizer, Ritva Peltomaa Speakers bureau: Boehringer Ingelmheim, Pfizer, Sanofi, Paid instructor for: Boehringer Ingelheim, Eli Lilly and Company, Janssen, Abbvie, UCB Pharma, Anniina Virtanen: None declared, Antti Kuuliala: None declared, Antti Kurttila: None declared, Anna Kinnunen: None declared, Marjatta Leirisalo-Repo: None declared, Olli Silvennoinen Speakers bureau: Pfizer, AbbVie, Pia Isomäki Speakers bureau: Abbvie, Eli Lilly and Company, Pfizer, Roche, Paid instructor for: Abbvie, Eli Lilly and Company, Pfizer, Roche, Grant/research support from: Pfizer
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Parisien, Jean-Patrick, Joe F. Lau, Jason J. Rodriguez, Christina M. Ulane, and Curt M. Horvath. "Selective STAT Protein Degradation Induced by Paramyxoviruses Requires both STAT1 and STAT2 but Is Independent of Alpha/Beta Interferon Signal Transduction." Journal of Virology 76, no. 9 (May 1, 2002): 4190–98. http://dx.doi.org/10.1128/jvi.76.9.4190-4198.2002.
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ABSTRACT The alpha/beta interferon (IFN-α/β)-induced STAT signal transduction pathway leading to activation of the ISGF3 transcription complex and subsequent antiviral responses is the target of viral pathogenesis strategies. Members of the Rubulavirus genus of the Paramyxovirus family of RNA viruses have acquired the ability to specifically target either STAT1 or STAT2 for proteolytic degradation as a countermeasure for evading IFN responses. While type II human parainfluenza virus induces STAT2 degradation, simian virus 5 induces STAT1 degradation. The components of the IFN signaling system that are required for STAT protein degradation by these paramyxoviruses have been investigated in a series of human somatic cell lines deficient in IFN signaling proteins. Results indicate that neither the IFN-α/β receptor, the tyrosine kinases Jak1 or Tyk2, nor the ISGF3 DNA-binding subunit, IFN regulatory factor 9 (IRF9), is required for STAT protein degradation induced by either virus. Nonetheless, both STAT1 and STAT2 are strictly required in the host cell to establish a degradation-permissive environment enabling both viruses to target their respective STAT protein. Complementation studies reveal that STAT protein-activating tyrosine phosphorylation and functional src homology 2 (SH2) domains are dispensable for creating a permissive STAT degradation environment in degradation-incompetent cells, but the N terminus of the missing STAT protein is essential. Protein-protein interaction analysis indicates that V and STAT proteins interact physically in vitro and in vivo. These results constitute genetic and biochemical evidence supporting a virus-induced, IFN-independent STAT protein degradation complex that contains at least STAT1 and STAT2.
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Ulane, Christina M., Alex Kentsis, Cristian D. Cruz, Jean-Patrick Parisien, Kristi L. Schneider, and Curt M. Horvath. "Composition and Assembly of STAT-Targeting Ubiquitin Ligase Complexes: Paramyxovirus V Protein Carboxyl Terminus Is an Oligomerization Domain." Journal of Virology 79, no. 16 (August 15, 2005): 10180–89. http://dx.doi.org/10.1128/jvi.79.16.10180-10189.2005.
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ABSTRACT Transcription regulators STAT1 and STAT2 are key components of the interferon signaling system leading to innate antiviral immunity. The related STAT3 protein is a regulator of interleukin-6-type cytokine signals and can contribute to both cell growth and death important for cancer gene regulation and tumor survival. These three STAT proteins are targeted for proteasome-mediated degradation by RNA viruses in the Rubulavirus genus of the Paramyxoviridae. A single viral protein, the V protein, assembles STAT-specific ubiquitin ligase complexes from cellular components. Simian virus 5 (SV5) targets STAT1, human parainfluenza virus 2 targets STAT2, and mumps virus targets both STAT1 and STAT3. Analysis of the V-dependent degradation complex (VDC) composition and assembly revealed several features contributing to targeting specificity. SV5 and mumps V proteins require STAT2 to recruit the STAT1 target, yet mumps V protein binds STAT3 independent of STAT1 and STAT2. All Rubulavirus V proteins tested require cellular DDB1 to target STATs for degradation but differ in the use of Roc1, which is essential for mumps V STAT3 targeting. Protein interaction analysis reveals that paramyxovirus V proteins can homo- and heterooligomerize and that the conserved cysteine-rich zinc-binding C-terminal domain is necessary and sufficient for oligomerization. Purified SV5 V protein spontaneously assembles into spherical macromolecular particles, and similar particles constitute SV5 and mumps VDC preparations.
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Yu, C. R., J. X. Lin, D. W. Fink, S. Akira, E. T. Bloom, and A. Yamauchi. "Differential utilization of Janus kinase-signal transducer activator of transcription signaling pathways in the stimulation of human natural killer cells by IL-2, IL-12, and IFN-alpha." Journal of Immunology 157, no. 1 (July 1, 1996): 126–37. http://dx.doi.org/10.4049/jimmunol.157.1.126.
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Abstract IL-2-, IL-12-, and IFN-alpha-mediated signaling pathways were analyzed in primary NK cells and in the NK3.3 cell line. Gel mobility shift and immunoprecipitation analyses revealed that in addition to activating STAT3 (signal transducer and activator of transcription-3) and STAT5, IL-2 induced tyrosine and serine phosphorylation of STAT1 alpha, which formed IFN-gamma-activated sequence-binding complexes by itself and with STAT3. Although IL-2 and IFN-alpha activated STAT1 alpha and STAT5, IL-2 predominantly activated STAT5, while IFN-alpha predominantly activated STAT1 alpha. IL-2 induced less STAT1 alpha activation and IFN-alpha induced greater STAT5 activation in NK3.3 cells compared with preactivated primary NK cells. In NK3.3 cells, IL-2 induced comparable formation of c-fos promoter sis-inducible element IFN-gamma-activated sequence-binding complexes containing STAT3 alone with complexes containing STAT3 and STAT1 alpha, while in preactivated primary NK cells, it preferentially induced complexes containing STAT3 and STAT1 alpha. Thus, signaling in NK3.3 cells is not always identical with that in primary NK cells. In contrast to IL-2 and IFN-alpha, IL-12 induced strong tyrosine phosphorylation of STAT4 and variable weak phosphorylation of STAT3. However, supershift analyses using the c-fos promoter sis-inducible element probe showed that IL-12 activated STAT4, STAT1 alpha, and STAT3, and induced complexes containing STAT4 only, STAT4 with STAT1 alpha, STAT3 with STAT1 alpha, or STAT1 alpha only in preactivated primary NK cells. STAT1 alpha activation by IL-12 correlated with increased phosphorylation of serine, but not tyrosine. Finally, IL-2 induced tyrosine phosphorylation of JAK1 and JAK3, while IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. Differential phosphorylation and consequent differential activation of both separate and overlapping STAT proteins by IL-2, IL-12, and IFN-alpha may provide a molecular basis for the similarities and differences in the actions of these cytokines on NK cells.
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Weber-Nordt, RM, C. Egen, J. Wehinger, W. Ludwig, V. Gouilleux-Gruart, R. Mertelsmann, and J. Finke. "Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines." Blood 88, no. 3 (August 1, 1996): 809–16. http://dx.doi.org/10.1182/blood.v88.3.809.809.
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Abstract Although various molecular mechanisms of STAT protein (signal transducers and activators of transcription) activation have been identified, little is known about the functional role of STAT-dependent transcriptional activation. Herein we report the constitutive nuclear localization, phosphorylation, and DNA-binding activity of STAT proteins in leukemia cells and lymphoma cell lines. With the use of oligonucleotide probes derived from the Fc gamma RI promoter, the beta- casein promoter and a STAT-binding element in the promoter of the Bci-2 gene constitutive activation of STAT proteins was detected in untreated acute T- and C/B-leukemia cells (3 of 5 and 12 of 19 patients, respectively). Supershift analyses using Stats 1–6 specific antisera showed the constitutive DNA binding activity of Stat5 in these cells. Confocal microscopy revealed the nuclear localization of Stat5 and Western blot analyses showed tyrosine phosphorylation of Stat5 in nuclear extracts of acute leukemia cells. In contrast, peripheral blood mononuclear cells did not display constitutive STAT-DNA interaction. Further studies were performed on freshly isolated acute myeloid leukemia cells as well as on cell line derived K562, lymphoblastoid cells (LCL), and Burkitt's lymphoma cells (BL). Fluorescence microscopy, gelshift, and supershift experiments showed the nuclear localization and constitutive DNA-binding activity of Stat5 in K562 cells. Stat1 and Stat3 were constitutively activated in freshly isolated AML cells (10 of 14 patients) and in Epstein Barr virus- positive or interleukin-10 expressing permanent LCL and BL cells. Thus, these data indicate a differential pattern of STAT protein activation in lymphoid or myeloid leukemia and in lymphoma cells.
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Weber-Nordt, RM, C. Egen, J. Wehinger, W. Ludwig, V. Gouilleux-Gruart, R. Mertelsmann, and J. Finke. "Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines." Blood 88, no. 3 (August 1, 1996): 809–16. http://dx.doi.org/10.1182/blood.v88.3.809.bloodjournal883809.
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Although various molecular mechanisms of STAT protein (signal transducers and activators of transcription) activation have been identified, little is known about the functional role of STAT-dependent transcriptional activation. Herein we report the constitutive nuclear localization, phosphorylation, and DNA-binding activity of STAT proteins in leukemia cells and lymphoma cell lines. With the use of oligonucleotide probes derived from the Fc gamma RI promoter, the beta- casein promoter and a STAT-binding element in the promoter of the Bci-2 gene constitutive activation of STAT proteins was detected in untreated acute T- and C/B-leukemia cells (3 of 5 and 12 of 19 patients, respectively). Supershift analyses using Stats 1–6 specific antisera showed the constitutive DNA binding activity of Stat5 in these cells. Confocal microscopy revealed the nuclear localization of Stat5 and Western blot analyses showed tyrosine phosphorylation of Stat5 in nuclear extracts of acute leukemia cells. In contrast, peripheral blood mononuclear cells did not display constitutive STAT-DNA interaction. Further studies were performed on freshly isolated acute myeloid leukemia cells as well as on cell line derived K562, lymphoblastoid cells (LCL), and Burkitt's lymphoma cells (BL). Fluorescence microscopy, gelshift, and supershift experiments showed the nuclear localization and constitutive DNA-binding activity of Stat5 in K562 cells. Stat1 and Stat3 were constitutively activated in freshly isolated AML cells (10 of 14 patients) and in Epstein Barr virus- positive or interleukin-10 expressing permanent LCL and BL cells. Thus, these data indicate a differential pattern of STAT protein activation in lymphoid or myeloid leukemia and in lymphoma cells.
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Gouilleux-Gruart, V., F. Gouilleux, C. Desaint, JF Claisse, JC Capiod, J. Delobel, R. Weber-Nordt, et al. "STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients." Blood 87, no. 5 (March 1, 1996): 1692–97. http://dx.doi.org/10.1182/blood.v87.5.1692.1692.
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Abstract A signal transduction pathway activated by many cytokines has recently been elaborated. The JAK kinases and the signal transducers and activators of transcription (STAT) factors have been found to be essential components. In this report, we describe the presence of constitutively activated STAT factors in peripheral blood cells from patients with acute leukemia. We used oligonucleotide probes from the beta-casein and IRF-1 gene promoters and the ISRE probe to detect STAT proteins in nuclear extracts from acute leukemia cells in bandshift assays. Specific DNA protein complex formation was observed with the probes from the beta-casein and IRF-1 gene promoters, but not with the ISRE oligonucleotide probe, when cell extracts from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were investigated. We used nonradioactive oligonucleotides as competitors to show the specificity of the complex formation. Specific antibodies directed against the individual STAT proteins were used in supershift experiments. STAT5- and STAT1-related factors were detected in ALL and STAT1-, STAT3-, and STAT5-related proteins were present in nuclear cell extracts from AML. Since the cells were not treated with cytokines before the nuclear proteins were extracted, we conclude that these factors are constitutively activated in vivo. It is likely that the constitutive activation of STAT proteins is a part of the events of leukemogenesis.
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Gouilleux-Gruart, V., F. Gouilleux, C. Desaint, JF Claisse, JC Capiod, J. Delobel, R. Weber-Nordt, et al. "STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients." Blood 87, no. 5 (March 1, 1996): 1692–97. http://dx.doi.org/10.1182/blood.v87.5.1692.bloodjournal8751692.
Full textAbstract:
A signal transduction pathway activated by many cytokines has recently been elaborated. The JAK kinases and the signal transducers and activators of transcription (STAT) factors have been found to be essential components. In this report, we describe the presence of constitutively activated STAT factors in peripheral blood cells from patients with acute leukemia. We used oligonucleotide probes from the beta-casein and IRF-1 gene promoters and the ISRE probe to detect STAT proteins in nuclear extracts from acute leukemia cells in bandshift assays. Specific DNA protein complex formation was observed with the probes from the beta-casein and IRF-1 gene promoters, but not with the ISRE oligonucleotide probe, when cell extracts from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were investigated. We used nonradioactive oligonucleotides as competitors to show the specificity of the complex formation. Specific antibodies directed against the individual STAT proteins were used in supershift experiments. STAT5- and STAT1-related factors were detected in ALL and STAT1-, STAT3-, and STAT5-related proteins were present in nuclear cell extracts from AML. Since the cells were not treated with cytokines before the nuclear proteins were extracted, we conclude that these factors are constitutively activated in vivo. It is likely that the constitutive activation of STAT proteins is a part of the events of leukemogenesis.
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Palosaari, Heidi, Jean-Patrick Parisien, Jason J. Rodriguez, Christina M. Ulane, and Curt M. Horvath. "STAT Protein Interference and Suppression of Cytokine Signal Transduction by Measles Virus V Protein." Journal of Virology 77, no. 13 (July 1, 2003): 7635–44. http://dx.doi.org/10.1128/jvi.77.13.7635-7644.2003.
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ABSTRACT Measles virus, a paramyxovirus of the Morbillivirus genus, is responsible for an acute childhood illness that infects over 40 million people and leads to the deaths of more than 1 million people annually (C. J. Murray and A. D. Lopez, Lancet 349:1269-1276, 1997). Measles virus infection is characterized by virus-induced immune suppression that creates susceptibility to opportunistic infections. Here we demonstrate that measles virus can inhibit cytokine responses by direct interference with host STAT protein-dependent signaling systems. Expression of the measles V protein prevents alpha, beta, and gamma interferon-induced transcriptional responses. Furthermore, it can interfere with signaling by interleukin-6 and the non-receptor tyrosine kinase, v-Src. Affinity purification demonstrates that the measles V protein associates with cellular STAT1, STAT2, STAT3, and IRF9, as well as several unidentified partners. Mechanistic studies indicate that while the measles V protein does not interfere with STAT1 or STAT2 tyrosine phosphorylation, it causes a defect in IFN-induced STAT nuclear accumulation. The defective STAT nuclear redistribution is also observed in measles virus-infected cells, where some of the STAT protein is detected in cytoplasmic bodies that contain viral nucleocapsid protein and nucleic acids. Interference with STAT-inducible transcription may provide a novel intracellular mechanism for measles virus-induced cytokine inhibition that links innate immune evasion to adaptive immune suppression.
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Zhao, Lan-Juan, Sheng-Fei He, Yuan Liu, Ping Zhao, Zhong-Qi Bian, and Zhong-Tian Qi. "Inhibition of STAT Pathway Impairs Anti-Hepatitis C Virus Effect of Interferon Alpha." Cellular Physiology and Biochemistry 40, no. 1-2 (2016): 77–90. http://dx.doi.org/10.1159/000452526.
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Background/Aims: Signal transducer and activator of transcription (STAT) pathway plays an important role in antiviral efficacy of interferon alpha (IFN-α). IFN-α is the main therapeutic against hepatitis C virus (HCV) infection. We explored effects of IFN-α on HCV replication and antiviral gene expression by targeting STAT. Methods: In response to IFN-α, STAT status, HCV replication, and antiviral gene expression were analyzed in human hepatoma Huh7.5.1 cells before and after cell culture-derived HCV infection. Results: IFN-α treatment induced expression and phosphorylation of STAT1 and STAT2 in Huh7.5.1 cells. Pretreatment of Huh7.5.1 cells with a mAb to IFN alpha receptor (IFNAR) 2 decreased IFN-α-dependent phosphorylation of STAT1 and STAT2, whereas pretreatment with an IFNAR1 mAb increased such phosphorylation, suggesting that IFNAR mediates IFN-α-triggered STAT signaling. During HCV infection, STAT1 and STAT2 phosphorylation could be rescued by IFN-α and IFN-α-induced phosphorylation of STAT1 and STAT2 was impaired. Inhibition of STAT pathway by Jak inhibitor I significantly enhanced HCV RNA replication and viral protein expression. Antiviral genes coding for IFN regulatory factor 9 and IFN-stimulated gene 15 were up-regulated by IFN-α during HCV infection but such up-regulation was abrogated by Jak inhibitor I. Conclusion: These results establish that activation of STAT pathway is essential for anti-HCV efficacy of IFN-α. Impairment of IFN-α-triggered STAT signaling by HCV may account for evading IFN-α response.
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Read, Kaitlin, Bharath Sreekumar, Michael Duane Powell, Devin Jones, and Kenneth J. Oestreich. "Ikaros zinc finger transcription factors as novel regulators of STAT factor activity." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 64.3. http://dx.doi.org/10.4049/jimmunol.202.supp.64.3.
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Abstract Cytokine signaling is important for the differentiation and function of a number of cell types, including lymphocyte populations. One mechanism by which cytokine signals are propagated is via phosphorylation-mediated activation of Signal Transducer and Activator of Transcription (STAT) factors, which directly regulate cell type-specific gene programs. We recently identified novel regulatory modules composed of STAT and Ikaros Zinc Finger (IkZF) transcription factors in CD4+ T cell populations. Specifically, we found that IkZF/STAT modules composed of Aiolos/STAT3 and Eos/STAT5 directly activate genes associated with T follicular helper (TFH) and T helper 1 (TH1) gene programs, respectively. Here, we extend these findings and show that IkZF factor expression correlates with STAT activation, suggesting that IkZF proteins may regulate STAT factor activity in CD4+ T cells. We find that overexpression of Aiolos, but not the IkZF factors Ikaros and Eos, results in increased STAT3 activation. Conversely, overexpression of Eos, but not Ikaros or Aiolos, results in increased activation of STAT5. Importantly, when we performed these studies using IkZF protein mutants incapable of interacting with STAT factors, the observed increase in STAT factor phosphorylation was lost. We also find that in CD4+ T cells, Eos deficiency correlates with reduced STAT5 activation, while Aiolos-deficient cells display reduced STAT3 activation. Finally, we observe differential IkZF factor expression across CD4+ T cell subsets. When coupled with known differences in STAT factor activation, these findings suggest that IkZF/STAT regulatory modules may broadly regulate T helper cell differentiation.
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Wang, Kathy S., Jerome Ritz, and David A. Frank. "IL-2 Induces STAT4 Activation in Primary NK Cells and NK Cell Lines, But Not in T Cells." Journal of Immunology 162, no. 1 (January 1, 1999): 299–304. http://dx.doi.org/10.4049/jimmunol.162.1.299.
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Abstract IL-2 exerts potent but distinct functional effects on two critical cell populations of the immune system, T cells and NK cells. Whereas IL-2 leads to proliferation in both cell types, it enhances cytotoxicity primarily in NK cells. In both T cells and NK cells, IL-2 induces the activation of STAT1, STAT3, and STAT5. Given this similarity in intracellular signaling, the mechanism underlying the distinct response to IL-2 in T cells and NK cells is not clear. In this study, we show that in primary NK cells and NK cell lines, in addition to the activation of STAT1 and STAT5, IL-2 induces tyrosine phosphorylation of STAT4, a STAT previously reported to be activated only in response to IL-12 and IFN-α. This activation of STAT4 in response to IL-2 is not due to the autocrine production of IL-12 or IFN-α. STAT4 activated in response to IL-2 is able to bind to a STAT-binding DNA sequence, suggesting that in NK cells IL-2 is capable of activating target genes through phosphorylation of STAT4. IL-2 induces the activation of Jak2 uniquely in NK cells, which may underlie the ability of IL-2 to activate STAT4 only in these cells. Although the activation of STAT4 in response to IL-2 occurs in primary resting and activated NK cells, it does not occur in primary resting T cells or mitogen-activated T cells. The unique activation of the STAT4-signaling pathway in NK cells may underlie the distinct functional effect of IL-2 on this cell population.
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Higashi, Takehiro, Junichi Tsukada, Takamitsu Mizobe, Fumihiko Mouri, Ai Matsuura, Yasuhiro Minami, Yasuhiro Yoshida, and Yoshiya Tanaka. "Synergistic Transactivation of the Sis-Inducible Element by STAT4/STAT3 Heterodimer in Cytokine Signal Cascade." Blood 108, no. 11 (November 16, 2006): 1119. http://dx.doi.org/10.1182/blood.v108.11.1119.1119.
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Abstract Signal transducer and activator of transcription (STAT) proteins are activated in response to cytokine stimulation. STAT3 is activated in response to interleukin (IL)-6 family of cytokines, following activation of Janus family of tyrosine kinases JAK1 and JAK2, which in turn phosphorylate STAT3 on tyrosine 705 (tyr-705). On the other hand, STAT4 is activated in response to IL-12 following activation of Janus family of tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693 (tyr-693). p38/MKK6 signaling pathway activated by IL-12 further phosphorylates STAT4 on serine 721 (ser-721). STAT4 plays a crucial role in the development of type-1 helper T (Th1) cells and production of interferon (IFN)-γ in response to IL-12. STAT4 is activated by IFN-α as well as IL-12. Several STAT heterodimer complexes have been demonstrated. Selective interactions of individual STATs upon complex formation might contribute to the transcriptional target specificity of cytokine and growth factor signaling. In the present study, we demonstrated that STAT4 forms a heterodimer with STAT3 to synergistically transactivate the high-affinity sis-inducible element (hSIE). A wild-type STAT3 expression vector Rc/CMV-STAT3WT and/or a wild-type STAT4 expression vector Rc/CMV-STAT4WT were cotransfected along with a hSIE reporter pGLmfoshSIE into Hep3B cells, and cells were treated with IL-6 and/or IFN-α. In the absence of overexpression of STAT3 and STAT4, little increase in hSIE activities was observed following treatment with the cytokines, However, when Rc/CMV-STAT3WT and -STAT4WT were cotransfected, transcriptional activities were synergistically enhanced following simultaneous stimulation with IL-6 and IFN-α. γ-interferon activated site (GAS) activity was not enhanced by the two STATs. No synergistic activation of hSIE was detected between STAT1 and STAT4, when a wild-type STAT1 expression vector was used instead of Rc/CMV-STAT3WT. Our mutational analyses further revealed that the synergy between STAT3 and STAT4 was almost completely abrogated by either mutation of STAT4 at tyr-693 or STAT3 at tyr-705, suggesting direct interaction of STAT3 with STAT4 as well as the importance of STAT tyrosine phosphorylation. However, mutation of STAT4 at ser-721 caused only a little suppression of the synergy. Similar results were obtained from mutation of STAT3 at ser-727. Our immunoprecipitation (IP)/western blot (WB) analyses exhibited that STAT4 forms a heterodimer with STAT3 in response to stimulation with IL-6 and IFN-α. Moreover, in electrophoretic mobility shift assay (EMSA), hSIE preferentially bound STAT3/STAT4 heterodimer. Based upon our results, STAT3 and STAT4 can form a heterodimer, which exhibits significantly different transcripitional activities and sequence preferences to bind its target DNA. Thus, the specificity in STAT signaling is at least partly dependent on selective interactions between individual STATs upon complex formation. STAT3/STAT4 heterodimer may play an important role in immune and inflammatory reactions in NK and T-cells in response to IL-12 and IFN-α.
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Standing, David, Emma Feess, Satvik Kodiyalam, Michael Kuehn, Zachary Hamel, Jaimie Johnson, Sufi Mary Thomas, and Shrikant Anant. "The Role of STATs in Ovarian Cancer: Exploring Their Potential for Therapy." Cancers 15, no. 9 (April 26, 2023): 2485. http://dx.doi.org/10.3390/cancers15092485.
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Ovarian cancer (OvCa) is a deadly gynecologic malignancy that presents many clinical challenges due to late-stage diagnoses and the development of acquired resistance to standard-of-care treatment protocols. There is an increasing body of evidence suggesting that STATs may play a critical role in OvCa progression, resistance, and disease recurrence, and thus we sought to compile a comprehensive review to summarize the current state of knowledge on the topic. We have examined peer reviewed literature to delineate the role of STATs in both cancer cells and cells within the tumor microenvironment. In addition to summarizing the current knowledge of STAT biology in OvCa, we have also examined the capacity of small molecule inhibitor development to target specific STATs and progress toward clinical applications. From our research, the best studied and targeted factors are STAT3 and STAT5, which has resulted in the development of several inhibitors that are under current evaluation in clinical trials. There remain gaps in understanding the role of STAT1, STAT2, STAT4, and STAT6, due to limited reports in the current literature; as such, further studies to establish their implications in OvCa are necessitated. Moreover, due to the deficiency in our understanding of these STATs, selective inhibitors also remain elusive, and therefore present opportunities for discovery.
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de Koning, JP, F. Dong, L. Smith, AM Schelen, RM Barge, DC van der Plas, LH Hoefsloot, B. Lowenberg, and IP Touw. "The membrane-distal cytoplasmic region of human granulocyte colony- stimulating factor receptor is required for STAT3 but not STAT1 homodimer formation." Blood 87, no. 4 (February 15, 1996): 1335–42. http://dx.doi.org/10.1182/blood.v87.4.1335.bloodjournal8741335.
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Signal transduction from the granulocyte colony-stimulating factor receptor (G-CSF-R) involves the activation of the Janus tyrosine kinase/signal transducer and activator of transcription (Jak/STAT) pathway. G-CSF induces tyrosine phosphorylation of Jak1, Jak2, STAT1, and STAT3. The membrane-proximal region of G-CSF-R is sufficient for activation of Jaks. It is still unclear how STAT proteins are activated by G-CSF-R. We investigated the possible involvement of the C-terminal region of G-CSF-R in the recruitment of STAT proteins using BAF3 cell transfectants expressing wild type (WT) G-CSF-R, C-terminal deletion mutants and tyrosine-to-phenylalanine substitution mutants. Electrophoretic mobility shift assays with STAT-binding oligonucleotides (m67) showed that activation of WT G-CSF-R induces three distinct STAT complexes, namely STAT3 homodimers, STAT1-STAT3 heterodimers, and STAT1 homodimers. However, STAT1 homodimers and STAT1- STAT3 heterodimers were predominantly formed after activation of a C- terminal deletion mutant d685, which lacks all four conserved cytoplasmic tyrosine residues, located at positions 704, 729, 744, and 764. Antiphosphotyrosine immunoblots of STAT3 immunoprecipitates showed that activation of WT G-CSF-R induced phosphorylation of STAT3. In contrast, no phosphorylation of STAT3 was observed after activation of deletion mutant d685. These findings establish that the C-terminal region of G-CSF-R plays a major role in the activation of STAT3. By using tyrosine-to-phenylalanine substitution mutants of G-CSF-R, we further show that tyrosine 704, present in a YXXQ consensus sequence shown to be essential for STAT3 binding to gp130, is not exclusively involved in the activation of STAT3 by G-CSF-R.
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Gowing, H., M. Lawler, A. Hagenbeek, SR McCann, DH Pamphilon, J. Hudson, H. van Weelden, E. Braakman, and AC Martens. "Effect of ultraviolet-B light on lymphocyte activity at doses at which normal bone marrow stem cells are preserved." Blood 87, no. 4 (February 15, 1996): 1635–43. http://dx.doi.org/10.1182/blood.v87.4.1635.bloodjournal8741635.
Full textAbstract:
Signal transduction from the granulocyte colony-stimulating factor receptor (G-CSF-R) involves the activation of the Janus tyrosine kinase/signal transducer and activator of transcription (Jak/STAT) pathway. G-CSF induces tyrosine phosphorylation of Jak1, Jak2, STAT1, and STAT3. The membrane-proximal region of G-CSF-R is sufficient for activation of Jaks. It is still unclear how STAT proteins are activated by G-CSF-R. We investigated the possible involvement of the C-terminal region of G-CSF-R in the recruitment of STAT proteins using BAF3 cell transfectants expressing wild type (WT) G-CSF-R, C-terminal deletion mutants and tyrosine-to-phenylalanine substitution mutants. Electrophoretic mobility shift assays with STAT-binding oligonucleotides (m67) showed that activation of WT G-CSF-R induces three distinct STAT complexes, namely STAT3 homodimers, STAT1-STAT3 heterodimers, and STAT1 homodimers. However, STAT1 homodimers and STAT1- STAT3 heterodimers were predominantly formed after activation of a C- terminal deletion mutant d685, which lacks all four conserved cytoplasmic tyrosine residues, located at positions 704, 729, 744, and 764. Antiphosphotyrosine immunoblots of STAT3 immunoprecipitates showed that activation of WT G-CSF-R induced phosphorylation of STAT3. In contrast, no phosphorylation of STAT3 was observed after activation of deletion mutant d685. These findings establish that the C-terminal region of G-CSF-R plays a major role in the activation of STAT3. By using tyrosine-to-phenylalanine substitution mutants of G-CSF-R, we further show that tyrosine 704, present in a YXXQ consensus sequence shown to be essential for STAT3 binding to gp130, is not exclusively involved in the activation of STAT3 by G-CSF-R.
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Owen, Katie L., Natasha K. Brockwell, and Belinda S. Parker. "JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression." Cancers 11, no. 12 (December 12, 2019): 2002. http://dx.doi.org/10.3390/cancers11122002.
Full textAbstract:
Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.
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Takeda, Takashi, Hirohisa Kurachi, Toshiya Yamamoto, Hiroaki Homma, Kenichirou Morishige, Akira Miyake, and Yuji Murata. "Participation of JAK, STAT and unknown proteins in human placental lactogen-induced signaling: a unique signaling pathway different from prolactin and growth hormone." Journal of Endocrinology 153, no. 1 (April 1997): R1—R3. http://dx.doi.org/10.1677/joe.0.153r001.
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Abstract The signal transduction mechanism involved in human placental lactogen (hPL) was studied. We have identified that hPL rapidly stimulated the tyrosine phosphorylation of at least 7 proteins including Janus Kinases (JAK1 and JAK2) and a signal transducer and activator of transcription protein (Stat3). This is the first evidence that the JAK-STAT pathway is involved in the hPL signaling. Moreover, two unknown proteins which were different from STAT proteins (Stat1, 3 and 5) in sizes were predominantly tyrosine-phosphorylated. Because human growth hormone (hGH) activates Stat1, 3, 5 and human prolactin (hPRL) activates Stat5, these results show that hPL uses a unique signal transduction pathway which is different from hGH and hPRL.
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Polak, Chernosky, Smigiel, Tamagno, and Jackson. "Balancing STAT Activity as a Therapeutic Strategy." Cancers 11, no. 11 (November 3, 2019): 1716. http://dx.doi.org/10.3390/cancers11111716.
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Driven by dysregulated IL-6 family member cytokine signaling in the tumor microenvironment (TME), aberrant signal transducer and activator of transcription (STAT3) and (STAT5) activation have been identified as key contributors to tumorigenesis. Following transformation, persistent STAT3 activation drives the emergence of mesenchymal/cancer-stem cell (CSC) properties, important determinants of metastatic potential and therapy failure. Moreover, STAT3 signaling within tumor-associated macrophages and neutrophils drives secretion of factors that facilitate metastasis and suppress immune cell function. Persistent STAT5 activation is responsible for cancer cell maintenance through suppression of apoptosis and tumor suppressor signaling. Furthermore, STAT5-mediated CD4+/CD25+ regulatory T cells (Tregs) have been implicated in suppression of immunosurveillance. We discuss these roles for STAT3 and STAT5, and weigh the attractiveness of different modes of targeting each cancer therapy. Moreover, we discuss how anti-tumorigenic STATs, including STAT1 and STAT2, may be leveraged to suppress the pro-tumorigenic functions of STAT3/STAT5 signaling.
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Zare, F., M. Dehghan-Manshadi, and A. Mirshafiey. "The signal transducer and activator of transcription factors lodge in immunopathogenesis of rheumatoid arthritis." Reumatismo 67, no. 4 (May 23, 2016): 127. http://dx.doi.org/10.4081/reumatismo.2015.851.
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Rheumatoid arthritisis (RA) is a chronic autoimmune disorder that affects ~1-2% of the world’s population and damages synovial joints. RA is characterized by inflammation, autoantibody production, cartilage and bone destruction and synovial hyperplasia. Inflammation induces systemic and articular synthesis of pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin-6 that play essential roles in joint and other organ damage in this disease. Considering the role of signal transducer and activator of transcription factors (STATs) in signaling of these cytokines, these proteins may be involved in the pathogenesis of RA. The expression and activity of STATs can contribute to the onset, progression and severity of RA. All STAT family members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) have been associated with autoimmune diseases, as highlighted in several studies. In this review we aim to describe the immunobiology of STATs and its family members and the role of these proteins in the immunopathogenesis of RA.
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Liang, Zengenni, Zhi-Hang Yuan, Yan Wang, Zhong-Hua Du, Jia-Jing Guo, Ling-Li Xia, and Yang Shan. "New Mechanistic Insight into the Protective Effects of Ganoderma lucidum Polysaccharides Against Palmitic Acid-Induced Cell Damage in Porcine Intestinal Epithelial Cell Line IPEC-J2." Natural Product Communications 17, no. 11 (November 2022): 1934578X2211281. http://dx.doi.org/10.1177/1934578x221128103.
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Ganoderma lucidum ( G. lucidum) is one of the well-known mushrooms in China, which has G. lucidum polysaccharides (GLP) that have been widely studied for various biological activities, such as antioxidant, antitumor, antiinflammatory, antiviral, antidiabetes, and immunomodulatory activities. A signal transducer and activator of transcription (STAT) signaling pathway is related to cell proliferation and apoptosis. The relationship between STAT and intestinal protection of GLP is still unknown. We studied the inhibitors AG490 in the STAT pathway and its downstream molecules to analyze the unique effects in the protection of GLP against palmitic acid (PA)-induced porcine intestinal epithelial cells (IPEC-J2) injury. Compared to PA treatment, GLP + PA obviously decreased Ca2+ concentration, H2O2 production, NF-E2-related factor 2 (Nrf2) nuclear translocation, STAT1 and STAT2 protein levels, and increased nuclear factor kappa-B (NF-κB) nuclear translocation and p-STAT3/STAT3 ratio in IPEC-J2 cells. After inhibition of STAT3 signaling, p-STAT3/STAT3 ratio, NF-κB nuclear translocation obviously decreased and Nrf2 nuclear translocation significantly increased in the GLP + PA group. The protection of GLP on proliferation and apoptosis of PA-induced IPEC-J2 cells was suppressed by inhibiting STAT3. The STAT3 pathway regulated the enterocyte-protective effects of GLP by modulating the nuclear translocation of Nrf2 and NF-κB. We provide new insights into the mechanism of STAT signaling for the protection of GLP on PA-induced intestinal epithelial cell injury.
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Matikainen, Sampsa, Timo Sareneva, Tapani Ronni, Anne Lehtonen, Päivi J. Koskinen, and Ilkka Julkunen. "Interferon- Activates Multiple STAT Proteins and Upregulates Proliferation-Associated IL-2R, c-myc, and pim-1 Genes in Human T Cells." Blood 93, no. 6 (March 15, 1999): 1980–91. http://dx.doi.org/10.1182/blood.v93.6.1980.406k20_1980_1991.
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Interferon- (IFN-) is a pleiotropic cytokine that has antiviral, antiproliferative, and immunoregulatory functions. There is increasing evidence that IFN- has an important role in T-cell biology. We have analyzed the expression ofIL-2R, c-myc, and pim-1 genes in anti-CD3–activated human T lymphocytes. The induction of these genes is associated with interleukin-2 (IL-2)–induced T-cell proliferation. Treatment of T lymphocytes with IFN-, IL-2, IL-12, and IL-15 upregulated IL-2R, c-myc, andpim-1 gene expression. IFN- also sensitized T cells to IL-2–induced proliferation, further suggesting that IFN- may be involved in the regulation of T-cell mitogenesis. When we analyzed the nature of STAT proteins capable of binding to IL-2R,pim-1, and IRF-1 GAS elements after cytokine stimulation, we observed IFN-–induced binding of STAT1, STAT3, and STAT4, but not STAT5 to all of these elements. Yet, IFN- was able to activate binding of STAT5 to the high-affinity IFP53 GAS site. IFN- enhanced tyrosine phosphorylation of STAT1, STAT3, STAT4, STAT5a, and STAT5b. IL-12 induced STAT4 and IL-2 and IL-15 induced STAT5 binding to the GAS elements. Taken together, our results suggest that IFN-, IL-2, IL-12, and IL-15 have overlapping activities on human T cells. These findings thus emphasize the importance of IFN- as a T-cell regulatory cytokine.
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Komyod, Waraporn, Uta-Maria Bauer, Peter C. Heinrich, Serge Haan, and Iris Behrmann. "Are STATS Arginine-methylated?" Journal of Biological Chemistry 280, no. 23 (April 12, 2005): 21700–21705. http://dx.doi.org/10.1074/jbc.c400606200.
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Transcription factors of the STAT (signal transducer and activator of transcription) family are important in signal transduction of cytokines. They are subject to post-translational modification by phosphorylation on tyrosine and serine residues. Recent evidence suggested that STATs are methylated on a conserved arginine residue within the N-terminal region. STAT arginine methylation has been described to be important for STAT function and loss of arginine methylation was discussed to be involved in interferon resistance of cancer cells. Here we provide several independent lines of evidence indicating that the issue of arginine methylation of STATs has to be reassessed. First, we show that treatment of melanoma and fibrosarcoma cells with inhibitors used to suppress methylation (N-methyl-2-deoxyadenosine, adenosine, dl-homocysteine) had profound and rapid effects on phosphorylation of STAT1 and STAT3 but also on p38 and Erk signaling cascades which are known to cross-talk with the Jak/STAT pathway. Second, we show that anti-methylarginine antibodies did not precipitate specifically STAT1 or STAT3. Third, we show that mutation of Arg31 to Lys led to destabilization of STAT1 and STAT3, implicating an important structural role of Arg31. Finally, purified catalytically active protein arginine methyltransferases (PRMT1, -2, -3, -4, and -6) did not methylate STAT proteins, and cotransfection with PRMT1 did not affect STAT1-controlled reporter gene activity. Taken together, our data suggest the absence of arginine methylation of STAT1 and STAT3.
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Giang, Nguyen Hoang, Nguyen Thanh Huyen, and Nguyen Thi Xuan. "Expression of genes involved in immune regulation in chronic myeloid leukemia." Vietnam Journal of Biotechnology 19, no. 1 (July 18, 2021): 51–60. http://dx.doi.org/10.15625/1811-4989/14672.
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Chronic myeloid leukemia (CML) is a blood cancer involved in abnormal proliferation of myeloid cells at all stages of differentiation. Translocation of regions of the BCR and ABL genes, leading to the fusion gene BCR-ABL, which forms the Philadelphia (Ph) chromosome, is the cause of more than 90% of CML. The BCR-ABL protein shows abnormal tyrosine kinase activity, leading to changes in proliferation signals including signal transducer and activator of transcriptions (STATs) and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and resulting in uncontrolled proliferation of myeloid cells. CTLA-4, PD-1 and LAG3 genes are known as immunosuppressive receptors playing important roles in controlling immune response by inhibiting activity of T helper cells. Klotho gene has anti-aging, anti-inflammatory and anti-cancer functions. STAT signaling pathway genes regulate cancer cell functions by their phosphorylation and IκB-α gene by degradation of its expression. In this study, we conducted experiments to determine mRNA expression of these genes on immune cells in CML patients by using realtime-PCR. Results showed a marked increase in the expression of STAT-1 and STAT-6 signaling genes and a decreased LAG3 expression in CML patients as compared with healthy controls. In addition, other gene expressions such as CTLA4, PD1, klotho, IκB-α, STAT3 and STAT5 were unaltered in CML cells. The abnormal increased expression of STAT1 and STAT6 genes indicated an important role of these signaling genes in regulating activity of immune cells, leading to pathogenesis and development of CML disease. The evidence suggested that STAT-1 and STAT-6 genes could be important and potential markers in early prognosis of CML.
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Bagby, Grover, Winifred Keeble, Tara Koretsky, Dylan Zodrow, Richard Jove, Laura Hays, and Hanqian Carlson. "Oxidative Stress Induces Binding of FANCD2 to STAT5 and Facilitates STAT5-Dependent Survival Signals." Blood 104, no. 11 (November 16, 2004): 33. http://dx.doi.org/10.1182/blood.v104.11.33.33.
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Abstract Fanconi anemia (FA) cells are hypersensitive to oxidative stress and exhibit aberrant STAT activation responses to defined extracellular proteins but whether these abnormalities are linked is unclear. Because oxidative stress is known to induce STAT activation, we hypothesized that proper STAT signaling responses in normal cells exposed to H2O2 require intact FA proteins. In fact, we found that FA-C, FA-G, and FA-D2 cells (fibroblasts) showed a significant increase in apoptosis after H2O2-exposure compared to retrovirally-complemented cells. H2O2 induced higher phospho-STAT5 (P-STAT5) expression in complemented cells than in mutant cells. Conversely, mutant cells expressed higher levels of P-STAT3 in both the ground state and after H2O2-induction than complemented cells. Aberrant STAT activation in FA mutant cells was shown to be both nucleus- and JAK2 kinase-dependent. Only low levels of STAT3 and STAT5 were induced in both mutant and complemented cytoplasts and AG490 (a Jak2 inhibitor) significantly suppressed H2O2-induced STAT5 responses. Seeking a direct role of FANCD2 in regulating proper STAT activation responses to H2O2, we carried out immunoprecipitation experiments (with an antibody to the N-terminal fragment of FANCD2) using PD20, a FA-D2 mutant cell line, and FANCD2 complemented PD20. In FANCD2-complemented and normal cells, anti-FANCD2 antibody immunoprecipitated STAT5. However, in mutant cells the same antibody immunoprecipitated STAT3, not STAT5. Thus, mutant (truncated) FANCD2 preferentially binds to and may activate STAT3 in the ground state. In fact, wild type FANCD2 also binds aberrantly to STAT3 in HSC536 (FA-C lymphoblasts) indicating that FANCC may influence the function of wild type FANCD2 and that binding of wild type FANCD2 to STAT3 does not require FANCD2 ubiquitinylation (FANCD2 is not ubiquitinylated in FA-C). Suspecting that in H2O2-exposed cells STAT5 signaling pathways lead to survival while STAT3 pathways lead to apoptosis, we transduced constitutively active mutants (*) of STATs 3 and 5 in mutant D2 and complemented cells. STAT3* increased apoptotic responses to H2O2 in complemented FA-D2 cells and STAT5* decreased apoptotic responses in H2O2-induced FA-D2 cells. In addition, the STAT5 inducible anti-apoptotic gene Bcl-XL was induced in H2O2-exposed complemented FA-D2 cells but not in FA-D2 cells. We conclude that FANCD2 functions to promote survival by ordering proper STAT signaling responses to oxidative stress and that this function of FANCD2 depends in part upon FA-C. We propose that FA cells are hypersensitive to oxidative stress in part because of imbalanced STAT signal transduction responses.
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Chen, Honglin, Jae Myun Lee, Yongsheng Zong, Michael Borowitz, Mun Hon Ng, Richard F. Ambinder, and S. Diane Hayward. "Linkage between STAT Regulation and Epstein-Barr Virus Gene Expression in Tumors." Journal of Virology 75, no. 6 (March 15, 2001): 2929–37. http://dx.doi.org/10.1128/jvi.75.6.2929-2937.2001.
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ABSTRACT Epstein-Barr virus (EBV) latency gene expression in lymphoblastoid cell lines is regulated by EBNA2. However, the factors regulating viral expression in EBV-associated tumors that do not express EBNA2 are poorly understood. In EBV-associated tumors, EBNA1 and frequently LMP1 are synthesized. We found that an alternative latent membrane protein 1 (LMP1) promoter, L1-TR, located within the terminal repeats is active in both nasopharyngeal carcinoma and Hodgkin's disease tissues. Examination of the L1-TR and the standard ED-L1 LMP1 promoters in electrophoretic mobility shift assays revealed that both promoters contain functional STAT binding sites. Further, both LMP1 promoters responded in reporter assays to activation of JAK-STAT signaling. Cotransfection of JAK1 or v-Src or treatment of cells with the cytokine interleukin-6 upregulated expression from ED-L1 and L1-TR reporter plasmids. Cotransfection of a dominant negative STAT3β revealed that STAT3 is likely to be the biologically relevant STAT for EBNA1 Qp and LMP1 L1-TR promoter regulation. In contrast, LMP1 expression from ED-L1 was not abrogated by STAT3β, indicating that the two LMP1 promoters are regulated by different STAT family members. Taken together with the previous demonstration of JAK-STAT activation of Qp driven EBNA1 expression, this places two of the EBV genes most commonly expressed in tumors under the control of the same signal transduction pathway. Immunohistochemical analyses of nasopharyngeal carcinoma tumors revealed that STAT3, STAT5, and STAT1 are constitutively activated in these tumors while STAT3 is constitutively activated in the malignant cells of Hodgkin's disease. We hypothesize that chronic or aberrant STAT activation may be both a necessary and predisposing event for EBV-driven tumorigenesis in immunocompetent individuals.
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Tuyt, Leonore M. L., Krista Bregman, Chantal Lummen, Wim H. A. Dokter, and Edo Vellenga. "Differential Binding Activity of the Transcription Factor LIL-Stat in Immature and Differentiated Normal and Leukemic Myeloid Cells." Blood 92, no. 4 (August 15, 1998): 1364–73. http://dx.doi.org/10.1182/blood.v92.4.1364.
Full textAbstract:
Abstract Cytokines and growth factors induce activation of the family of signal transducers and activators of transcription (Stats) that directly activate gene expression. Recently, constitutively activated Stat1, Stat3, and Stat5 were identified in nuclear extracts of acute myeloid leukemia (AML) patients, suggesting involvement of constitutive Stat activity in the events of leukemogenesis. In the present study, blasts of nine AML cases were investigated for the constitutive binding activity of the recently identified transcription factor LIL-Stat (LPS- and IL-1-inducible Stat). Band-shift assays were performed using the LPS-and IL-1-responsive element (LILRE) oligonucleotide, a gamma interferon activation site-like site that is present in the human IL-1β promoter. Constitutive LIL-Stat binding activity was observed in three leukemic cell lines and in seven out of nine AML cases. Transient transfection studies with a reporter plasmid containing three sequential LIL-Stat binding sites showed distinct transcriptional activity of LIL-Stat only in those AML blasts that constitutively expressed LIL-Stat. In CD34+ cells LIL-Stat also constitutively bound to its consensus sequence. However, when these cells were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and stem cell factor (SCF) for differentiation along the monocytic lineage, the LIL-Stat binding activity disappeared totally. In agreement with these findings neither mature monocytes nor granulocytes showed constitutive or inducible LIL-Stat binding activity. We conclude that the LIL-Stat transcription factor is constitutively activated in undifferentiated and leukemic hematopoietic cells, but not in mature cells. This may suggest a role for this transcription factor in the process of differentiation. © 1998 by The American Society of Hematology.
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Tuyt, Leonore M. L., Krista Bregman, Chantal Lummen, Wim H. A. Dokter, and Edo Vellenga. "Differential Binding Activity of the Transcription Factor LIL-Stat in Immature and Differentiated Normal and Leukemic Myeloid Cells." Blood 92, no. 4 (August 15, 1998): 1364–73. http://dx.doi.org/10.1182/blood.v92.4.1364.416k34_1364_1373.
Full textAbstract:
Cytokines and growth factors induce activation of the family of signal transducers and activators of transcription (Stats) that directly activate gene expression. Recently, constitutively activated Stat1, Stat3, and Stat5 were identified in nuclear extracts of acute myeloid leukemia (AML) patients, suggesting involvement of constitutive Stat activity in the events of leukemogenesis. In the present study, blasts of nine AML cases were investigated for the constitutive binding activity of the recently identified transcription factor LIL-Stat (LPS- and IL-1-inducible Stat). Band-shift assays were performed using the LPS-and IL-1-responsive element (LILRE) oligonucleotide, a gamma interferon activation site-like site that is present in the human IL-1β promoter. Constitutive LIL-Stat binding activity was observed in three leukemic cell lines and in seven out of nine AML cases. Transient transfection studies with a reporter plasmid containing three sequential LIL-Stat binding sites showed distinct transcriptional activity of LIL-Stat only in those AML blasts that constitutively expressed LIL-Stat. In CD34+ cells LIL-Stat also constitutively bound to its consensus sequence. However, when these cells were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and stem cell factor (SCF) for differentiation along the monocytic lineage, the LIL-Stat binding activity disappeared totally. In agreement with these findings neither mature monocytes nor granulocytes showed constitutive or inducible LIL-Stat binding activity. We conclude that the LIL-Stat transcription factor is constitutively activated in undifferentiated and leukemic hematopoietic cells, but not in mature cells. This may suggest a role for this transcription factor in the process of differentiation. © 1998 by The American Society of Hematology.