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Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activation

Oncogene volume 20, pages 252–259 (2001)Cite this article

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.

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Acknowledgements

We are greatly indebted to Dr A Atfi, Dr MJ Birnbaum, Dr BM Burgering, Dr H Clevers, Dr GM Cooper, Dr C Gespach, Dr W Ogawa and Dr J Pouysségur for providing us with plasmids. We thank B Jacquin for secretarial support.

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Authors and Affiliations

  1. INSERM U.402, Faculté de Médecine Saint-Antoine, Paris, France

    Christèle Desbois-Mouthon, Axelle Cadoret, Marie-José Blivet-Van Eggelpoël, France Bertrand, Gisèle Cherqui & Jacqueline Capeau

  2. INSERM U.129, ICGM, Paris, France

    Christine Perret

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Desbois-Mouthon, C., Cadoret, A., Blivet-Van Eggelpoël, MJ. et al. Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activation. Oncogene 20, 252–259 (2001). https://doi.org/10.1038/sj.onc.1204064

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