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Stabilization of the Ras oncoprotein by the insulin-like growth factor 1 receptor during anchorage-independent growth

M Gatzka1, M Prisco, R Baserga

  • 1Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107, USA.

Cancer Research
|August 17, 2000
PubMed

Insights

Mouse embryo cells lacking insulin-like growth factor 1 receptor (IGF-IR) resist Ras transformation. IGF-IR signaling stabilizes Ras, enabling transformation, suggesting new therapeutic targets for Ras-driven cancers.

Area of Science:

  • Cell Biology
  • Oncology
  • Molecular Biology

Background:

  • Insulin-like growth factor 1 receptor (IGF-IR) plays a role in cell growth and transformation.
  • Ras oncoproteins are frequently activated in human cancers.
  • IGF-IR signaling is crucial for cellular transformation induced by oncogenes.

Purpose of the Study:

  • To investigate the mechanism by which IGF-IR signaling influences Ras-mediated cellular transformation.
  • To determine the role of IGF-IR in stabilizing Ras oncoprotein levels.
  • To explore alternative transformation mechanisms involving Ras and IGF-IR.

Main Methods:

  • Utilized R- cells (3T3 cells with disrupted IGF-IR genes) and R-Ras cells (R- cells expressing activated Ha-Ras).
  • Assessed colony formation in soft agar under anchorage-independent conditions.
  • Quantified Ras oncoprotein levels in monolayer and anchorage-independent cultures with and without truncated IGF-IR signaling.

Main Results:

  • R- cells are refractory to Ras-induced transformation.
  • Ras oncoprotein is rapidly degraded in R-Ras cells under anchorage-independent conditions.
  • Signaling from a truncated IGF-IR stabilizes Ras, enabling transformation in R- cells.

Conclusions:

  • IGF-IR signaling is essential for maintaining Ras oncoprotein stability and mediating Ras-driven transformation.
  • Ras transformation of cells lacking IGF-IR is prevented by Ras degradation.
  • These findings reveal a generalized mechanism for Ras transformation and suggest potential therapeutic strategies targeting Ras in tumors.

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