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Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor

Leonard Girnita1, Ada Girnita, Olle Larsson

  • 1Department of Oncology and Pathology, Division of Cellular and Molecular Tumor Pathology, Cancer Center Karolinska, R8:04, Karolinska Hospital, SE-171 76 Stockholm, Sweden.

Proceedings of the National Academy of Sciences of the United States of America
|June 25, 2003
PubMed

Insights

The tumor suppressor p53 indirectly regulates insulin-like growth factor 1 receptor (IGF-1R) levels by influencing Mdm2 E3 ligase activity. Mdm2 ubiquitinates and degrades IGF-1R, impacting cancer cell growth.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • The insulin-like growth factor 1 receptor (IGF-1R) is a receptor tyrosine kinase vital for cancer cell growth and survival.
  • The tumor suppressor p53's interaction with IGF-1R expression is complex and not fully understood.
  • Wild-type p53 typically represses IGF-1R transcription, yet overexpression can lead to high IGF-1R levels.

Purpose of the Study:

  • To elucidate the mechanism by which p53 influences IGF-1R expression.
  • To investigate the role of Mdm2 in the p53-IGF-1R regulatory pathway.
  • To determine if Mdm2 directly mediates IGF-1R ubiquitination and degradation.

Main Methods:

  • Inhibition of p53 in human malignant melanoma cells.
  • Co-inhibition of Mdm2 alongside p53.
  • UV irradiation of human melanocytes to up-regulate p53.
  • In vitro ubiquitination assays using Mdm2 and IGF-1R.
  • Assessment of IGF-1R ubiquitination, degradation, and protein levels.

Main Results:

  • p53 inhibition led to IGF-1R ubiquitination and degradation, independent of p53 status.
  • Mdm2 co-inhibition prevented IGF-1R down-regulation.
  • UV-induced p53 up-regulation increased IGF-1R levels.
  • Mdm2 directly binds to IGF-1R and mediates its ubiquitination in vitro.
  • Basal IGF-1R ubiquitination in untreated cells was Mdm2-dependent.

Conclusions:

  • Mdm2 acts as an E3 ligase for IGF-1R, targeting it for proteasomal degradation.
  • p53 indirectly regulates IGF-1R expression by sequestering Mdm2 in the nucleus.
  • This p53-Mdm2-IGF-1R axis provides a novel mechanism for controlling IGF-1R levels and cell growth.

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