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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

A novel role for IGF-1R in p53-mediated apoptosis through translational modulation of the p53-Mdm2 feedback loop

Lei Xiong1, Fei Kou, Ying Yang

  • 1Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

The Journal of Cell Biology
|September 12, 2007
PubMed

Insights

Insulin-like growth factor 1 receptor (IGF-1R) regulates p53 protein levels by controlling its translation. IGF-1R inhibition impairs DNA damage response, reducing cancer cell apoptosis and survival.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Insulin-like growth factor 1 receptor (IGF-1R) plays a critical role in cancer cell proliferation, survival, and pathophysiology.
  • IGF-1R signaling is a target in cancer therapy.
  • The tumor suppressor protein p53 is crucial for the apoptotic response to DNA damage.

Purpose of the Study:

  • To investigate the novel function of IGF-1R in p53-dependent apoptosis.
  • To elucidate the mechanism by which IGF-1R influences p53 protein levels and function.
  • To determine the impact of IGF-1R inhibition on DNA damage-induced apoptosis.

Main Methods:

  • Utilized Igf-1r(-/-) mouse embryonic fibroblasts and tumor cells.
  • Administered IGF-1R inhibitors to assess effects on p53 and Mdm2.
  • Analyzed protein synthesis, stability, ubiquitination, and translational control.
  • Investigated the role of 5' untranslated regions of p53 and Mdm2 mRNA and eukaryotic translation initiation factor 4F.

Main Results:

  • Inhibition or loss of IGF-1R activity reduced the translational synthesis of p53 and Mdm2 proteins.
  • IGF-1R inhibition increased p53 protein stability by decreasing ubiquitination.
  • IGF-1R activity maintains low p53 levels by decreasing p53 synthesis, making it insensitive to DNA damage.
  • Reduced accumulation and apoptosis of DNA-damage-induced p53 were observed in Igf-1r(-/-) cells or cells treated with IGF-1R inhibitor.
  • IGF-1R inhibition suppressed p53 and Mdm2 translation via a gene-specific mechanism involving their 5' untranslated regions and the eukaryotic translation initiation factor 4F complex.

Conclusions:

  • IGF-1R plays an unexpected role in the translational control of p53 and Mdm2.
  • IGF-1R activity is essential for efficient p53-mediated apoptosis following DNA damage.
  • Targeting IGF-1R impacts translational regulation, affecting cancer cell response to genotoxic stress.

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