Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling.
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.
Jenkins
Brendan J
BJ
Ludwig Institute for Cancer Research, Parkville, Vic 3050, Australia.
Grail
Dianne
D
Nheu
Thao
T
Najdovska
Meri
M
Wang
Bo
B
Waring
Paul
P
Inglese
Melissa
M
McLoughlin
Rachel M
RM
Jones
Simon A
SA
Topley
Nicholas
N
Baumann
Heinz
H
Judd
Louise M
LM
Giraud
Andrew S
AS
Boussioutas
Alex
A
Zhu
Hong-Jian
HJ
Ernst
Matthias
M
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*
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