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See detailOncostatin M up-regulates the ER chaperone Grp78/BiP in liver cells
Vollmer, Stefan UL; Haan, Claude UL; Behrmann, Iris UL

in Biochemical Pharmacology (2010), 80(12), 2066-2073

OSM, a cytokine of the IL-6-type cytokine family, regulates inflammatory processes (like the acute phase response), tissue remodeling, angiogenesis, cell differentiation and proliferation. Inflammation is ... [more ▼]

OSM, a cytokine of the IL-6-type cytokine family, regulates inflammatory processes (like the acute phase response), tissue remodeling, angiogenesis, cell differentiation and proliferation. Inflammation is discussed to favor carcinogenesis and the inflammatory cytokine OSM was lately described to up-regulate HIF-1α, whose up-regulation is also observed in many cancers. In this study we demonstrate that OSM, and to a lesser degree IL-6, induces the expression of Grp78/BiP, an ER chaperone associated with tumor development and poor prognosis in cancer. In contrast, IFN-γ or TNF-α had no effect on Grp78 expression. The up-regulation seems to be specific to liver cells, as it occurs in hepatocytes and hepatoma cells but not in prostate, melanoma, breast or kidney cells. OSM does not lead to up-regulation of Grp94, enhanced XBP-1 mRNA splicing or phosphorylation of eIF2α, indicating that it is not associated to a general ER stress response. Analysis of the underlying mechanism showed that Grp78 is up-regulated by transcriptional processes which are to the greater part, though not completely, dependent on MEK/Erk activation. © 2010 Elsevier Inc. [less ▲]

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See detailHypoxia-inducible factor 1alpha is up-regulated by oncostatin M and participates in oncostatin M signaling
Vollmer, Stefan UL; Kappler, Valérie; Kaczor, Jakub UL et al

in Hepatology (Baltimore, Md.) (2009), 2009(3),

The interleukin-6-type cytokine oncostatin M (OSM) acts via the Janus kinase/signal transducer and activator of transcription pathway as well as via activation of mitogen-activated protein kinases and is ... [more ▼]

The interleukin-6-type cytokine oncostatin M (OSM) acts via the Janus kinase/signal transducer and activator of transcription pathway as well as via activation of mitogen-activated protein kinases and is known to critically regulate processes such as liver development and regeneration, hematopoiesis, and angiogenesis, which are also determined by hypoxia with the hypoxia-inducible factor 1alpha (HIF1alpha) as a key component. Here we show that treatment of hepatocytes and hepatoma cells with OSM leads to an increased protein level of HIF1alpha under normoxic and hypoxic conditions. Furthermore, the OSM-dependent HIF1alpha increase is mediated via Janus kinase/signal transducer and activator of transcription 3 and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 pathways. OSM-mediated HIF1alpha up-regulation did not result from an increase in HIF1alpha protein stability but from increased transcription from the HIF1alpha gene. In addition, we show that the OSM-induced HIF1alpha gene transcription and the resulting enhanced HIF1alpha protein levels are important for the OSM-dependent vascular endothelial growth factor and plasminogen activator inhibitor 1 gene induction associated with several diseases. Conclusion: HIF1alpha levels increase significantly after treatment of hepatocytes and hepatoma cells with OSM, and HIF1alpha contributes to OSM downstream signaling events, pointing to a cross-talk between cytokine and hypoxia signaling in processes such as liver development and regeneration. (HEPATOLOGY 2009.). [less ▲]

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