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Growth factor-specific regulation of insulin receptor substrate-1 expression in MCF-7 breast carcinoma cells: effects

Claudine Lassarre1, Jean-Marc Ricort

  • 1Institut National de la Santé et de la Recherche Médicale, Unité 515, Hôpital Saint-Antoine, Paris, France.

Endocrinology
|September 10, 2003
PubMed

Insights

Growth factors like FGF and EGF can increase Insulin Receptor Substrate-1 (IRS-1) protein, influencing Insulin-like Growth Factor (IGF) signaling. This modulation is linked to the MAPK pathway and protein synthesis, impacting cell growth and cancer.

Area of Science:

  • Cellular Biology
  • Molecular Endocrinology
  • Cancer Signaling Pathways

Background:

  • Insulin-like Growth Factors (IGFs) are critical regulators of cell proliferation, differentiation, and tumorigenesis.
  • Insulin receptor substrate-1 (IRS-1) is a pivotal protein within the IGF signaling cascade, particularly in estrogen-dependent breast cancer cells (MCF-7).

Purpose of the Study:

  • To investigate how fibroblast growth factor (FGF), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF) modulate IRS-1 protein expression and the IGF-I signaling pathway.
  • To elucidate the specific signaling pathways (MAPK, PI 3-kinase) involved in growth factor-mediated regulation of IRS-1.

Main Methods:

  • Treatment of MCF-7 cells with FGF, EGF, and PDGF.
  • Assessment of IRS-1 protein expression levels.
  • Analysis of MAPK and PI 3-kinase signaling pathway activation.
  • Investigation of de novo protein synthesis requirements.
  • Use of constitutively active MAPK kinase for sustained pathway activation.

Main Results:

  • FGF and EGF increased IRS-1 protein levels; PDGF had no significant effect.
  • The increase in IRS-1 by EGF and FGF was dependent on the MAPK pathway and de novo protein synthesis, but independent of PI 3-kinase.
  • Sustained MAPK activity, induced by FGF or constitutively active MAPK kinase, led to a stronger increase in IRS-1 expression compared to transient MAPK activation (EGF).
  • Pretreatment with EGF, FGF, or PDGF reduced IGF-I-induced IRS-1 tyrosine phosphorylation.
  • EGF and PDGF pretreatment inhibited IGF-I-induced PI 3-kinase activity, while FGF did not.

Conclusions:

  • Different growth factors differentially modulate IRS-1 protein content and IGF-I signaling.
  • The FGF-induced increase in IRS-1 can compensate for reduced IRS-1 tyrosine phosphorylation, maintaining normal IGF-I-induced PI 3-kinase activity.
  • MAPK pathway activation, particularly sustained activity, plays a key role in regulating IRS-1 expression, influencing cancer cell signaling.

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