Signaling network of Oncostatin M pathway

Dey, Gourav; Radhakrishnan, Aneesha; Syed, Nazia; Thomas, Joji Kurian; Nadig, Arpitha; Srikumar, Kotteazeth; Mathur, Premendu P.; Pandey, Akhilesh; Lin, Sze‐Kwan; Raju, Rajesh; Prasad, T. S. Keshava

doi:10.1007/s12079-012-0186-y

Cited by 48 publications

(45 citation statements)

References 43 publications

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“…Interestingly, the untreated day 21 cells had higher basal level of phosphorylated form of STAT1 which could be due to use of oncostatin M (OSM), an IL-6 family of cytokine that shares signaling pathway with STAT1. However, both IFN-α and OSM have distinct receptors and downstream target genes resulting in specific biological outcomes (Darnell, Kerr et al 1994; Heinrich, Behrmann et al 1998; Dey, Radhakrishnan et al 2013). Our results indicated that the JAK-STAT pathway can be triggered by IFN-α in pluripotent stem cell-derived endoderm-hepatic lineage cells.…”

Section: Resultsmentioning

confidence: 99%

“…During IFN-α treatment, these cytokine-infused cocktails could influence the gene expression profile by altering the activation of respective signaling pathways. For instance, oncostatin M used during day 16 to 21 of differentiation can bind to heterodimeric cell surface receptors- gp130 and either leukemia inhibiting factor receptor (LIFR) or OSM receptor-beta (OSMR-beta) resulting in activation of JAK-STAT, MAPK, and PI3K/AKT pathways (Heinrich, Behrmann et al 1998; Van Wagoner, Choi et al 2000; Arita, South et al 2008; Dey, Radhakrishnan et al 2013). This variable was taken into account while calculating gene transcription specifically altered upon IFN treatment by comparing between IFN-α untreated (control) and treated cells of each endoderm, hepatoblast and immature hepatocyte phases.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of type I interferon pathway during hepatic differentiation of human pluripotent stem cells and hepatitis C virus infection

et al. 2015

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Pluripotent stem cells are being actively studied as a cell source for regenerating damaged liver. For long term survival of engrafting cells in the body, not only do the cells have to execute liver-specific function but also withstand the physical strains and invading pathogens. The cellular innate immune system orchestrated by the interferon (IFN) pathway provides the first line of defense against pathogens. The objective of this study is to assess the innate immune function as well as to systematically profile the IFN-induced genes during hepatic differentiation of pluripotent stem cells. To address this objective, we derived endodermal cells (day 5 post-differentiation), hepatoblast (day 15) and hepatocyte-like cells (day 21) from human embryonic stem cells (hESC). Day 5, 15 and 21 cells were stimulated with IFN-α and subjected to IFN pathway analysis. Transcriptome analysis was carried out by RNA sequencing. The results showed that the IFN-α treatment activated STAT-JAK pathway in differentiating cells. Transcriptome analysis indicated stage specific expression of classical and non-classical IFN-stimulated genes (ISGs). Subsequent validation confirmed the expression of novel ISGs including RASGRP3, CLMP and TRANK1 by differentiated hepatic cells upon IFN treatment. Hepatitis C virus replication in hESC-derived hepatic cells induced the expression of ISGs – LAMP3, ETV7, RASGRP3, and TRANK1. The hESC-derived hepatic cells contain intact innate system and can recognize invading pathogens. Besides assessing the tissue-specific functions for cell therapy applications, it may also be important to test the innate immune function of engrafting cells to ensure adequate defense against infections and improve graft survival.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Characterization of type I interferon pathway during hepatic differentiation of human pluripotent stem cells and hepatitis C virus infection

et al. 2015

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“…12 The OSMR complex activates Janus Kinases 1 and 2 (JAK1 and JAK2), which in turn activate Signal Transducer and Activator of Transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)-AKT-mediated signaling cascades. [13][14][15][16][17][18] Elevated levels of OSM in the TME are associated with highly aggressive metastatic cancers, increased risk of tumor recurrence, and a poor prognosis. [19][20][21][22][23][24] In breast cancer, OSM is concentrated at the invasive edges of highly metastatic tumors where cells often display mesenchymal cell characteristics and express the cancer stem cell marker CD44.…”

Section: Introductionmentioning

confidence: 99%

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-b (TGF-b) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-b/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-b receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSMinduced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.

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“…OSM has been demonstrated to act through Stat signaling (Stats 1 and 3) and Erk signaling pathways (reviewed by 26 ). Chronic exposure of keratinocytes to OSM increased phospho-Stat1, -Stat3, and -Erk, as expected ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Deducing signaling pathways from parallel actions of arsenite and antimonite in human epidermal keratinocytes

Phillips

Cánovas

Rea

et al. 2020

Sci Rep

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Inorganic arsenic oxides have been identified as carcinogens in several human tissues, including epidermis. Due to the chemical similarity between trivalent inorganic arsenic (arsenite) and antimony (antimonite), we hypothesized that common intracellular targets lead to similarities in cellular responses. Indeed, transcriptional and proteomic profiling revealed remarkable similarities in differentially expressed genes and proteins resulting from exposure of cultured human epidermal keratinocytes to arsenite and antimonite in contrast to comparisons of arsenite with other metal compounds. These data were analyzed to predict upstream regulators and affected signaling pathways following arsenite and antimonite treatments. A majority of the top findings in each category were identical after treatment with either compound. inspection of the predicted upstream regulators led to previously unsuspected roles for oncostatin M, corticosteroids and ephrins in mediating cellular response. The influence of these predicted mediators was then experimentally verified. Together with predictions of transcription factor effects more generally, the analysis has led to model signaling networks largely accounting for arsenite and antimonite action. the striking parallels between responses to arsenite and antimonite indicate the skin carcinogenic risk of exposure to antimonite merits close scrutiny.Chronic exposure to inorganic arsenic, primarily in water supplies, has numerous deleterious effects on humans, including cancer at several anatomic sites 1 . Many mechanisms have been proposed for these effects, indicating possible interference of arsenic with a variety of signaling pathways 2 to which epigenetic changes may contribute 3 . Proteins with vicinal thiols, including zinc finger DNA repair proteins 4 , are particularly attractive as potential targets with deleterious downstream effects. Continuing exposure of large populations has evoked considerable effort to elucidate the broad consequences for health and the mechanisms that lead to their manifestation.Also of concern, including human therapeutic treatment for leishmaniasis 5 , considerable exposure occurs to inorganic antimony, a metalloid immediately below arsenic in the periodic table to which it exhibits chemical similarity 6 . The presence of antimony is increasing in the environment through use in small arms ammunition, as a catalyst in plastic, as a flame retardant, and through watershed pollution by mining waste or by recycling operations. This has raised concern for public health, sustainable agriculture and ecosystem effects 7,8 . Inasmuch as antimony trioxide is a rodent carcinogen 9 , finding commonalities in actions of antimonite (SbIII) and arsenite (AsIII) would assist in understanding their mechanisms of action in vivo.Human epidermis is a known target for carcinogenic effects of arsenic. Cultured human epidermal keratinocytes, a model system for studies of effects of chemicals on epidermis, have been shown to respond similarly to treatment with arsenite and an...

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Signaling network of Oncostatin M pathway

Cited by 48 publications

References 43 publications

Characterization of type I interferon pathway during hepatic differentiation of human pluripotent stem cells and hepatitis C virus infection

Characterization of type I interferon pathway during hepatic differentiation of human pluripotent stem cells and hepatitis C virus infection

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

Deducing signaling pathways from parallel actions of arsenite and antimonite in human epidermal keratinocytes

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