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Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis

T Bowman1, M A Broome, D Sinibaldi

  • 1Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, FL 33612, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 19, 2001
PubMed

Insights

Platelet-derived growth factor (PDGF) signaling activates Src kinases, which then activate Signal transducer and activator of transcription 3 (STAT3). This pathway, crucial for cell growth and transformation, involves c-Myc as a key downstream effector.

Area of Science:

  • Cellular signaling pathways
  • Oncogenesis
  • Molecular biology

Background:

  • Signal transducer and activator of transcription (STAT) proteins mediate cytokine and growth factor signaling, including platelet-derived growth factor (PDGF).
  • Src family kinases are involved in PDGF-induced mitogenesis and STAT signaling.
  • Stat3 plays a role in Src oncoprotein-mediated cell transformation, but the precise mechanisms are unclear.

Purpose of the Study:

  • To elucidate the signaling mechanisms by which STAT pathways contribute to mitogenesis and transformation.
  • To define the role of c-Myc as a downstream effector in the PDGF-Src-STAT3 pathway.
  • To investigate the interplay between Src, STAT3, and c-Myc in normal cell growth and oncogenic transformation.

Main Methods:

  • Utilized dominant-negative Stat3beta protein to disrupt Stat3 signaling in NIH 3T3 fibroblasts.
  • Employed ectopic c-Myc expression and c-myc gene knockout to assess c-Myc's role.
  • Inhibited Src family kinases using the pharmacologic agent SU6656.

Main Results:

  • Disruption of Stat3 signaling suppressed c-Myc expression and inhibited v-Src-induced transformation.
  • Ectopic c-Myc expression partially reversed Stat3 inhibition, indicating c-Myc is a downstream effector.
  • c-myc gene knockout fibroblasts were resistant to v-Src transformation.
  • Inhibition of Src kinases blocked PDGF-induced Stat3 activation.
  • PDGF-induced mitogenesis was inhibited by Stat3 disruption but reversed by c-Myc expression.

Conclusions:

  • Delineated the signaling pathway PDGF --> Src --> Stat3 --> Myc, critical for normal mitogenesis.
  • Demonstrated that this pathway is subverted during Src-mediated transformation.
  • Established c-Myc as a key downstream mediator of Stat3 signaling in both normal cell growth and oncogenesis.

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