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Regulation of c-myc expression by PDGF through Rho GTPases
M Chiariello1, M J Marinissen, J S Gutkind
1Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
Src family protein-tyrosine kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation and apoptosis. Surprisingly, these kinases also participate in mitogenic signalling by receptors that themselves exhibit an intrinsic protein-tyrosine kinase activity, including those for platelet-derived growth factor (PDGF), epidermal growth factor and colony-stimulating factor-1. Indeed, Src kinases are strictly required for the nuclear expression of the c-myc proto-oncogene and thus for DNA synthesis in response to PDGF. However, the nature of the signalling pathways by which Src kinases participate in the induction of c-myc expression by tyrosine kinase receptors is still unknown. Here we show that PDGF enhances c-myc expression and stimulates the c-myc promoter in a Src-dependent manner, and that neither Ras nor the mitogen-activated protein kinase pathway mediate these effects. In contrast, we present evidence that PDGF stimulates Vav2 through Src, thereby initiating the activation of a Rac-dependent pathway that controls the expression of the c-myc proto-oncogene.
Insights
Src kinases are crucial for c-myc gene expression and DNA synthesis in response to platelet-derived growth factor (PDGF). This study reveals a novel pathway involving Vav2 and Rac, independent of Ras and MAPK, mediating these PDGF-induced effects.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Oncogene research
Background:
- Src family protein-tyrosine kinases regulate vital cellular processes like adhesion, cell cycle, and apoptosis.
- These kinases are unexpectedly involved in mitogenic signaling initiated by receptor tyrosine kinases (RTKs).
- Src kinases are essential for c-myc proto-oncogene expression and DNA synthesis following platelet-derived growth factor (PDGF) stimulation.
Purpose of the Study:
- To elucidate the signaling mechanisms by which Src kinases mediate c-myc induction by RTKs.
- To investigate the role of Ras and mitogen-activated protein kinase (MAPK) pathways in PDGF-induced c-myc expression.
- To identify alternative signaling cascades activated by Src in response to PDGF.
Main Methods:
- Investigated PDGF-induced c-myc promoter activity in a Src-dependent manner.
- Assessed the involvement of Ras and MAPK pathways in PDGF signaling.
- Examined the activation of Vav2 and Rac signaling cascades following PDGF stimulation.
Main Results:
- PDGF stimulation enhances c-myc expression and promoter activity, dependent on Src kinases.
- The Ras and MAPK pathways do not mediate PDGF-induced c-myc expression.
- PDGF activates Vav2 through Src, leading to Rac-dependent control of c-myc proto-oncogene expression.
Conclusions:
- Src kinases are essential mediators of PDGF-induced c-myc expression.
- A novel signaling pathway involving Src, Vav2, and Rac regulates c-myc expression independently of Ras/MAPK.
- This discovery sheds light on the intricate mechanisms controlling proto-oncogene expression in response to growth factors.