Author: ["Brendan J Jenkins","Dianne Grail","Thao Nheu","Meri Najdovska","Bo Wang","Paul Waring","Melissa Inglese","Rachel M McLoughlin","Simon A Jones","Nicholas Topley","Heinz Baumann","Louise M Judd","Andrew S Giraud","Alex Boussioutas","Hong-Jian Zhu","Matthias Ernst"]
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Abstract
The latent transcription factor Stat3 is activated by gp130, the common receptor for the interleukin (IL)-6 cytokine family and other growth factor and cytokine receptors. Ligand-induced dimerization of gp130 leads to activation of the Stat1, Stat3 and Shp2-Ras-Erk signaling pathways. Here we assess genetically the contribution of exaggerated Stat3 activation to the phenotype of gp130Y757F/Y757F mice, in which a knock-in mutation disrupts the negative feedback mechanism on gp130-dependent Stat signaling. Compared to gp130Y757F/Y757F mice, reduced Stat3 activation in gp130Y757F/Y757FStat3+/− mice increased their lifespan, prevented splenomegaly, normalized exaggerated hepatic acute-phase response and lymphocyte trafficking, and suppressed the growth of spontaneously arising gastric adenomas in young mice. These lesions share histological features of gastric polyps in aging mice with monoallelic null mutations in Smad4, which encodes the common transducer for transforming growth factor (TGF)-β signaling. Indeed, hyperactivation of Stat3 desensitizes gp130Y757F/Y757F cells to the cytostatic effect of TGF-β through transcriptional induction of inhibitory Smad7, thereby providing a novel link for cross-talk between Stat and Smad signaling in gastric homeostasis.Cite this article
Jenkins, B., Grail, D., Nheu, T. et al. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling. Nat Med 11, 845–852 (2005). https://doi.org/10.1038/nm1282 