title: GSK3 protein positively regulates type I insulin-like growth factor receptor through forkhead transcription factors FOXO1/3/4.
abstract: Glycogen synthase kinase-3 (GSK3) has either tumor-suppressive roles or pro-tumor roles in different types of human tumors. A number of GSK3 targets in diverse signaling pathways have been uncovered, such as tuberous sclerosis complex subunit 2 and β-catenin. The O subfamily of forkhead/winged helix transcription factors (FOXO) is known as tumor suppressors that induce apoptosis. In this study, we find that FOXO binds to type I insulin-like growth factor receptor (IGF-IR) promoter and stimulates its transcription. GSK3 positively regulates the transactivation activity of FOXO and stimulates IGF-IR expression. Although kinase-dead GSK3β cannot up-regulate IGF-IR, the constitutively active GSK3β induces IGF-IR expression in a FOXO-dependent manner. Serum starvation or Akt inhibition leads to an increase in IGF-IR expression, which could be blunted by GSK3 inhibition. GSK3β knockdown or GSK3 inhibitor suppresses IGF-I-induced IGF-IR, Akt, and ERK1/2 phosphorylation. Moreover, knockdown of GSK3β or FOXO1/3/4 leads to a decrease in cellular proliferation and abrogates IGF-I-induced hepatoma cell proliferation. These results suggest that GSK3 and FOXO may positively regulate IGF-I signaling and hepatoma cell proliferation.
authors: From the State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu 610041.
authors: Xiaodong
authors: X
authors: Huo
authors: From the State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu 610041.
authors: Shu
authors: S
authors: Liu
authors: From the State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu 610041.
authors: Ting
authors: T
authors: Shao
authors: the Laboratory of Stem Cell Biology, West China Hospital, Chengdu 610041.
authors: Hui
authors: H
authors: Hua
authors: From the State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu 610041.
authors: Qingbin
authors: Q
authors: Kong
authors: the School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, and.
authors: Jiao
authors: J
authors: Wang
authors: the Cancer Center, West China Hospital, Chengdu 610041, China.
authors: Ting
authors: T
authors: Luo
authors: From the State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu 610041, jyangfu@scu.edu.cn.
authors: Yangfu
authors: Y
authors: Jiang
mesh_terms: D015153:Blotting, Western; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008957:Models, Genetic; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018797:Cell Cycle Proteins; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C108803:FOXO4 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3
keywords: Cancer; FOXO; Glycogen Synthase Kinase 3 (GSK-3); Insulin-like Growth Factor (IGF); Receptor Tyrosine Kinase