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Analysis of the c-KIT Ligand Promoter Using Chromatin Immunoprecipitation
Published on: June 27, 2017
GSK3 protein positively regulates type I insulin-like growth factor receptor through forkhead transcription factors
Xiaodong Huo1, Shu Liu1, Ting Shao1
1From the State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu 610041.
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.
Insights
Glycogen synthase kinase-3 (GSK3) and FOXO transcription factors promote hepatoma cell proliferation by stimulating insulin-like growth factor-I receptor (IGF-IR) expression and signaling.
Area of Science:
- Molecular Biology
- Cancer Research
- Signal Transduction
Background:
- Glycogen synthase kinase-3 (GSK3) exhibits context-dependent roles in human tumors.
- Forkhead/winged helix transcription factors (FOXO) subfamily members function as tumor suppressors.
- GSK3 and FOXO pathways are implicated in various cellular processes, including proliferation and apoptosis.
Purpose of the Study:
- To investigate the role of GSK3 and FOXO in regulating insulin-like growth factor-I receptor (IGF-IR) expression.
- To elucidate the mechanism by which GSK3 influences FOXO activity and IGF-IR transcription.
- To determine the impact of GSK3 and FOXO on hepatoma cell proliferation and IGF-I signaling.
Main Methods:
- Luciferase reporter assays to assess promoter activity.
- Western blotting to detect protein expression and phosphorylation.
- Knockdown studies using small interfering RNA (siRNA) targeting GSK3β and FOXO family members.
- Cell proliferation assays and IGF-I stimulation experiments.
Main Results:
- FOXO directly binds to the IGF-IR promoter and stimulates its transcription.
- GSK3 positively regulates FOXO's transactivation activity, leading to increased IGF-IR expression.
- GSK3 inhibition or knockdown suppresses IGF-I-induced signaling (Akt, ERK1/2 phosphorylation) and hepatoma cell proliferation.
- Knockdown of GSK3β or FOXO abrogates IGF-I-induced proliferation in hepatoma cells.
Conclusions:
- GSK3 and FOXO act in concert to positively regulate IGF-I signaling.
- The GSK3-FOXO axis promotes hepatoma cell proliferation through IGF-IR.
- Targeting GSK3 or FOXO may represent a therapeutic strategy for hepatoma.
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