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Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling

Nature Medicine volume 11, pages 845–852 (2005)Cite this article

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.

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Figure 1: Extragastric pathologies in gp130Y757F/Y757F mice result from Stat3 hyperactivation.
Figure 2: gp130-dependent Stat3 hyperactivation promotes gastric adenomatous hyperplasia in gp130Y757F/Y757F mice.
Figure 3: Stat3-mediated desensitization of TGF-β signaling.
Figure 4: Stat3-dependent transcriptional induction of Smad7.
Figure 5: Smad7 siRNA treatment reverts Stat3-dependent desensitization of TGF-β signaling.
Figure 6: Epistatic interactions between Stat3 and Smad signaling in gastric cancer.

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Acknowledgements

We are indebted to S. Rose-John and G. Begley for the gift of HYPER-IL-6 and recombinant human IL-6, respectively. We thank A. Moustakas and R. Heuchel for making available the luciferase reporter constructs p(CAGA)12-luc and pSmad7-luc, and J. Wade for assistance in preparing plasma samples. We thank V. Feakes for histology, J. Stickland for photography and A. Burgess and J. Heath for critical reading of the manuscript. This work was supported by grants from the National Health and Medical Research Council of Australia to B.J.J., M.E., A.S.G. and H.J.Z., and by the Wellcome Trust to R.M.M.

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Author notes

  1. Brendan J Jenkins and Hong-Jian Zhu: These authors contributed equally to this work.

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Parkville, 3050, Vic, Australia

    Brendan J Jenkins, Dianne Grail, Thao Nheu, Meri Najdovska, Bo Wang, Melissa Inglese, Hong-Jian Zhu & Matthias Ernst

  2. Department of Pathology, Peter MacCallum Cancer Institute, East Melbourne, 3002, Vic, Australia

    Paul Waring

  3. Department of Medical Biochemistry and Immunology and Institute of Nephrology, Cardiff University, School of Medicine, Heath Park, Cardiff, CF14 4XN, UK

    Rachel M McLoughlin, Simon A Jones & Nicholas Topley

  4. Department of Molecular and Cellular Biology, MRC 308, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA

    Heinz Baumann

  5. Department of Medicine, University of Melbourne, Footscray, 3011, Vic, Australia

    Louise M Judd, Andrew S Giraud & Alex Boussioutas

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Correspondence to Hong-Jian Zhu or Matthias Ernst.

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Supplementary information

Supplementary Fig. 1

Stat1 and Stat3 tyrosine phosphorylation in mouse embryonic fibroblasts (MEFs) stimulated with HYPER-IL-6. (PDF 109 kb)

Supplementary Fig. 2

Impaired TGF-β-dependent transcriptional activation of the artificial Smad3 reporter p(CAGA)12-luc in gastric epithelial IMGE-5 cells following activation of the gp130(Y757F) receptor. (PDF 85 kb)

Supplementary Table 1

Primers used in Real-time and Semi-quantitative RT-PCR assays. (PDF 74 kb)

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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

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