title: Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling.
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 gp130 (Y757F/Y757F) mice, in which a knock-in mutation disrupts the negative feedback mechanism on gp130-dependent Stat signaling. Compared to gp130 (Y757F/Y757F) mice, reduced Stat3 activation in gp130 (Y757F/Y757F) Stat3(+/-) 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)-beta signaling. Indeed, hyperactivation of Stat3 desensitizes gp130 (Y757F/Y757F) cells to the cytostatic effect of TGF-beta through transcriptional induction of inhibitory Smad7, thereby providing a novel link for cross-talk between Stat and Smad signaling in gastric homeostasis.
authors.affiliation: Ludwig Institute for Cancer Research, Parkville, Vic 3050, Australia.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
authors.forename: Dianne
authors.initials: D
authors.lastname: Grail
authors.forename: Thao
authors.initials: T
authors.lastname: Nheu
authors.forename: Meri
authors.initials: M
authors.lastname: Najdovska
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Waring
authors.forename: Melissa
authors.initials: M
authors.lastname: Inglese
authors.forename: Rachel M
authors.initials: RM
authors.lastname: McLoughlin
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.forename: Heinz
authors.initials: H
authors.lastname: Baumann
authors.forename: Louise M
authors.initials: LM
authors.lastname: Judd
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Giraud
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Zhu
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
mesh_terms: D000236:Adenoma / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D006652:Histological Techniques; D015151:Immunoblotting; D051379:Mice; D008817:Mice, Mutant Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051906:Smad7 Protein / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D015533:Transcriptional Activation / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C494200:Il6st protein, mouse; D050796:STAT3 Transcription Factor; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta; D050822:Cytokine Receptor gp130