Cross talk between the insulin and Wnt signaling pathways: evidence from intestinal endocrine L cells.
The proglucagon gene (glu) encodes the incretin hormone glucagon-like peptide-1 (GLP-1), produced in the intestinal endocrine L cells. We found previously that the bipartite transcription factor beta-catenin/T cell factor (cat/TCF), the major effector of the canonical Wnt signaling pathway, activates intestinal glu expression and GLP-1 production. We show here that 100 nm insulin stimulated glu expression and enhanced GLP-1 content in the intestinal GLUTag L cell line as well as in primary fetal rat intestinal cell cultures. Increased intestinal glu mRNA expression and GLP-1 content were also observed in vivo in hyperinsulinemic MKR mice. In the GLUTag cells, insulin-induced activation of glu expression occurred through the same TCF site that mediates cat/TCF activation. Phosphatidylinositol 3-kinase inhibition, but not protein kinase B inhibition, attenuated the stimulation by insulin. Furthermore, nuclear beta-catenin content in the intestinal L cells was increased by insulin. Finally, insulin enhanced the binding of TCF-4 and beta-catenin to the TCF site in the glu promoter G2 enhancer element, as determined by quantitative chromatin immunoprecipitation assay. Collectively, these findings indicate that enhancement of beta-catenin nuclear translocation and cat/TCF binding are among the mechanisms underlying cross talk between the insulin and Wnt signaling pathways in intestinal endocrine L cells.
Yi
Fenghua
F
Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
Sun
Jane
J
Lim
Gareth E
GE
Fantus
I George
IG
Brubaker
Patricia L
PL
Jin
Tianru
T
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D006224:Cricetinae; D004742:Enhancer Elements, Genetic; D019858:Enteroendocrine Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005260:Female; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D011247:Pregnancy; D052336:Proglucagon / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051820:TCF Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
D007328:Insulin; D012333:RNA, Messenger; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D052336:Proglucagon