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Functional cooperation of RKTG with p53 in tumorigenesis and epithelial-mesenchymal transition

Yuhui Jiang1, Xiaoduo Xie, Zhigang Li

  • 1Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.

Cancer Research
|March 10, 2011
PubMed

Insights

Raf kinase trapping to Golgi (RKTG) cooperates with p53 to suppress tumors. Loss of RKTG and p53 promotes skin cancer and epithelial-mesenchymal transition (EMT) by affecting AKT and GSK3β signaling.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • Raf kinase trapping to Golgi (RKTG) negatively regulates Ras/Raf/MEK/ERK and GPCR Gβγ signaling, suggesting a tumor suppressor role.
  • p53 is a well-established tumor suppressor gene; p53 heterozygous mice are prone to developing tumors.
  • RKTG-deficient mice exhibit increased susceptibility to skin cancer upon carcinogen administration.

Purpose of the Study:

  • To investigate the in vivo tumor suppressor function of RKTG and its cooperation with p53.
  • To explore the role of RKTG and p53 in regulating AKT, GSK3β phosphorylation, and epithelial-mesenchymal transition (EMT).

Main Methods:

  • Analysis of RKTG-null mouse embryonic fibroblasts and RKTG-null/p53 heterozygous mice.
  • Stimulation with lysophosphatidic acid (LPA) and epidermal growth factor (EGF).
  • Western blot analysis for phosphorylated AKT, GSK3β, p53, p21, p16, and β-catenin.
  • Assessment of hyperplasia, EMT, and loss of heterozygosity (LOH) of p53.
  • Gene knockdown and overexpression studies in A431 and HepG2 cells.

Main Results:

  • LPA stimulation in RKTG-null cells induced hyperphosphorylation of AKT and GSK3β, increased p53 phosphorylation and accumulation, and upregulated p21 and p16.
  • RKTG-null and p53 heterozygous mice developed spontaneous skin tumors with hyperplasia and EMT, associated with p53 LOH.
  • RKTG knockdown enhanced LPA-induced AKT/GSK3β phosphorylation, β-catenin accumulation, and EMT in p53-mutated cells; these effects were counteracted by p53 overexpression.
  • Simultaneous silencing of RKTG and p53 in HepG2 cells maximized LPA-induced AKT phosphorylation and EMT features.

Conclusions:

  • RKTG functions as an in vivo tumor suppressor, cooperating with p53 in preventing tumorigenesis.
  • p53 possesses an EMT checkpoint function, and its loss, combined with RKTG loss, drives EMT and tumor progression.
  • Targeting RKTG and p53 pathways may offer therapeutic strategies for cancers exhibiting EMT.

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