Signaling pathways associated with colonic mucosa hyperproliferation in mice overexpressing gastrin precursors.
MTI/G-Gly mice and hGAS mice, overexpressing glycine-extended gastrin (G-Gly) and progastrin, respectively, display colonic mucosa hyperplasia, hyperproliferation, and an increased susceptibility to intestinal neoplasia. Here, we have used these transgenic mice to analyze in vivo the modulation of intracellular signaling pathways that may be responsible for the proliferative effects of gastrin precursors. The expression, activation, and localization of signaling and cell-to-cell adhesion molecules were studied using immunofluorescence and Western blot techniques on colonic tissues derived from MTI/G-Gly, hGAS, or wild-type FVB/N mice. These analyses revealed an up-regulation of Src tyrosine kinase and related signaling pathways [phosphatidyl inositol 3'-kinase (PI3K)/Akt, Janus-activated kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3, and extracellular-signal regulated kinases (ERK)] in both MTI/G-Gly and hGAS mice compared with the wild-type control animals as well as an overexpression of transforming growth factor-alpha (TGF-alpha). In contrast, overexpression of the gastrin precursors did not affect the activation status of STAT1 nor the expression and the distribution of adhesion proteins (focal adhesion kinase, cadherins, and catenins). We report for the first time that the transition from a normal colonic epithelium to a hyperproliferative epithelium in MTI/G-Gly and hGAS mice may be a consequence of the up-regulation of Src, PI3K/Akt, JAK2, STAT3, ERKs, and TGF-alpha. Deregulation of cell adhesion, a late event in tumor progression, does not occur in these transgenic models.
Ferrand
Audrey
A
Institut National de la Sante et de la Recherche Medicale Unit 531, Groupe de Recherche de Biologie et Pathologie Digestives, Hopital Rangueil, Toulouse, France.
Bertrand
Claudine
C
Portolan
Ghislaine
G
Cui
Guanglin
G
Carlson
Jane
J
Pradayrol
Lucien
L
Fourmy
Daniel
D
Dufresne
Marlene
M
Wang
Timothy C
TC
Seva
Catherine
C
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D049109:Cell Proliferation; D003106:Colon / Q000201:enzymology / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005755:Gastrins / Q000378:metabolism*; D006965:Hyperplasia / Q000201:enzymology / Q000473:pathology; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology*; D053614:Janus Kinase 2; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
D004268:DNA-Binding Proteins; D005755:Gastrins; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; C013706:big gastrin; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D019061:src-Family Kinases