Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activation
Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activation
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DOI：
10.1038/sj.onc.1204064
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发表时间：
2001-01-11
期刊：
影响因子：
8
通讯作者：
Capeau, J
中科院分区：
文献类型：
--
作者：
Desbois-Mouthon, C;Cadoret, A;Capeau, J
我们研究了胰岛素/胰岛素样生长因子 - 1（IGF - 1）调节通路和β - 连环蛋白调节通路之间的相互作用，这两种通路都被怀疑在肝癌发生中起作用。在HepG2细胞中，胰岛素和IGF - 1使Lef/Tcf依赖的荧光素酶报告基因的转录增加了3 - 4倍。这种刺激是通过磷脂酰肌醇3 - 激酶（PI 3 - K）/Akt的激活以及糖原合成酶激酶 - 3β（GSK - 3β）的抑制来介导的，因为胰岛素和IGF - I的作用可被PI 3 - K或Akt的显性负性突变体以及一种不可抑制的GSK - 3β所抑制。在抑制GSK - 3β的同时，胰岛素和IGF - I增加了β - 连环蛋白的细胞质水平。PI 3 - K/Akt/GSK - 3β通路并不是介导胰岛素和IGF - 1对Lef/Tcf依赖转录刺激的唯一通路。Ras信号通路也是必需的，因为（i）胰岛素和IGF - I的刺激作用可被显性负性Ras或MEK1抑制剂PD98059所抑制，并且（ii）活化的Ha - Ras或组成型活性MEK与无催化活性的GSK - 3β协同刺激Lef/Tcf依赖的转录。这项研究首次提供了证据，表明胰岛素和IGF - I通过在PI 3 - K下游分支的两个信号级联来刺激β - 连环蛋白通路，这两个级联涉及GSK - 3β的抑制和Ras的激活。这些发现首次证明了胰岛素和IGF - I在肝癌细胞中激活β - 连环蛋白通路的能力，从而为这些因子在肝癌发生中的作用提供了新的见解。
We examined the interplay between the insulin/LGF-1- and beta -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-3 beta (GSK-3 beta) since the effects of insulin and IGF-I were inhibited by dominant-negative mutants of PI 3-K or Akt and an uninhibitable GSK-3 beta. Together with inhibiting GSK-3 beta, insulin and IGF-I increased the cytoplasmic levels of beta -catenin, The PI 3-K/Akt/GSK-3 beta 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-I were inhibited by dominant-negative Ras or the MEK1 inhibitor PD98059 and (ii) activated Ha-Res or constitutively active MEK synergized with catalytically inactive GSK-3 beta to stimulate Lef/Tcf-dependent transcription. This study provides the first evidence that insulin and IGF-I stimulate the beta -catenin pathway through tw a signalling cascades bifurcating downstream of PI 3-K and involving GSK-3 beta inhibition and Ras activation. These findings demonstrate for the first time the ability of insulin and IGF-I to activate the beta -catenin pathway in hepatoma cells and thereby provide new insights into the role of these factors in hepatocarcinogenesis.