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Loss of insulin-like growth factor II receptor expression promotes growth in cancer by increasing intracellular signaling from both IGF-I and insulin receptors.

Abstract
The insulin-like growth factor-II receptor (IGF-IIR) is frequently mutated or deleted in some malignant human tumors, suggesting that the IGF-IIR is a tumor suppressor. However, the exact mechanism by which IGF-IIR suppresses growth in tumors has not been definitively established. We demonstrate that IGF-IIR-deficient murine L cells (D9) have higher growth rates than IGF-IIR-positive L cells (Cc2) in response to IGF-II. IGF-II levels are higher in growth-conditioned medium from D9 versus Cc2 cells. Receptor neutralization studies and measurements of insulin receptor substrate 1 phosphorylation confirm that the enhanced growth of D9 cells is due to increased stimulation of the IGF-I and insulin receptors by IGF-II. In contrast, the levels of secreted latent and active transforming growth factor beta (TGF-beta) are similar for both D9 and Cc2 cells, indicating that the slower growth of Cc2 cells is not due to activation of latent TGF-beta by IGF-IIR and growth inhibition. The results directly demonstrate that down regulation of the IGF-IIR promotes the growth of transformed D9 cells by sustaining IGF-II, which binds to and activates IGF-IR and insulin receptor to increase intracellular growth signals.
AuthorsC Osipo, S Dorman, A Frankfater
JournalExperimental cell research (Exp Cell Res) Vol. 264 Issue 2 Pg. 388-96 (Apr 1 2001) ISSN: 0014-4827 [Print] United States
PMID11262195 (Publication Type: Journal Article)
CopyrightCopyright 2001 Academic Press.
Chemical References
  • Culture Media, Conditioned
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Phosphoproteins
  • Receptor, IGF Type 2
  • Transforming Growth Factor beta
  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1
  • Receptor, Insulin
Topics
  • Animals
  • Cattle
  • Cell Division
  • Culture Media, Conditioned
  • Humans
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor II (biosynthesis, pharmacology)
  • Intracellular Fluid
  • L Cells (Cell Line)
  • Mice
  • Phosphoproteins (metabolism)
  • Receptor, IGF Type 1 (metabolism)
  • Receptor, IGF Type 2 (genetics, metabolism)
  • Receptor, Insulin (metabolism)
  • Signal Transduction (physiology)
  • Transforming Growth Factor beta (metabolism)

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