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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.
Summary
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.