We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activation.
- Authors
Desbois-Mouthon, Christèle; Cadoret, Axelle; Blivet-Van Eggelpoël, Marie-José; Bertrand, France; Cherqui, Gisèle; Perret, Christine; Capeau, Jacqueline
- Abstract
We examined the interplay between the insulin/IGF-1- and β-catenin-regulated pathways, both of which are suspected to play a role in hepatocarcinogenesis. Insulin and IGF-1 stimulated the transcription of a Lef/Tcf-dependent luciferase reporter gene by 3–4-fold in HepG2 cells. This stimulation was mediated through the activation of phosphatidylinositol 3-kinase (PI 3-K)/Akt and the inhibition of glycogen synthase kinase-3β (GSK-3β) since the effects of insulin and IGF-1 were inhibited by dominant-negative mutants of PI 3-K or Akt and an uninhibitable GSK-3β. Together with inhibiting GSK-3β, insulin and IGF-1 increased the cytoplasmic levels of β-catenin. The PI 3-K/Akt/GSK-3β pathway was not the sole to mediate insulin and IGF-1 stimulation of Lef/Tcf-dependent transcription. The Ras signalling pathway was also required as (i) the stimulatory effects of insulin and IGF-1 were inhibited by dominant-negative Ras or the MEK1 inhibitor PD98059 and (ii) activated Ha-Ras or constitutively active MEK1 synergized with catalytically inactive GSK-3β to stimulate Lef/Tcf-dependent transcription. This study provides the first evidence that insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades bifurcating downstream of PI 3-K and involving GSK-3β inhibition and Ras activation. These findings demonstrate for the first time the ability of insulin and IGF-1 to activate the β-catenin pathway in hepatoma cells and thereby provide new insights into the role of these factors in hepatocarcinogenesis. Oncogene (2001) 20, 252–259.
- Subjects
INSULIN; SOMATOMEDIN; RAS oncogenes; PROTEIN kinases
- Publication
Oncogene, 2001, Vol 20, Issue 2, p252
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1204064