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Cooperating oncogenes converge to regulate cyclin/cdk complexes
A C Lloyd1, F Obermüller, S Staddon
1Imperial Cancer Research Fund (ICRF), London, UK.
Genes & Development
|March 1, 1997
Summary
Oncogene cooperation drives synergistic cell transformation. Raf kinase activation halts cell cycle via p21(CiP1), but SV40 large T antigen or mutant p53 overrides this arrest, promoting proliferation by modulating cyclin/cdk activity.
Area of Science:
- Cellular biology
- Molecular oncology
- Cancer research
Background:
- Oncogene cooperation is crucial for synergistic cell transformation.
- Understanding the molecular mechanisms of oncogene cooperation is key to cancer research.
Purpose of the Study:
- To investigate the molecular mechanisms underlying synergistic transformation of primary rat Schwann cells by cooperating oncogenes.
- To elucidate the roles of Raf kinase, SV40 large T antigen (LT), and p53 in cell cycle regulation during transformation.
Main Methods:
- Activation of an inducible Raf kinase in primary rat Schwann cells.
- Coexpression of SV40 large T (LT) or a dominant-negative p53 mutant.
- Analysis of cell cycle arrest, p21(CiP1) induction, and cyclin/cdk activity.
Main Results:
- Raf kinase activation induced cell cycle arrest at G1 by upregulating p21(CiP1), inhibiting cyclin/cdk activity.
- SV40 LT or dominant-negative p53 abolished p21(CiP1) induction and growth arrest.
- Raf and LT cooperated to increase cyclin A/cdk2 activity, stimulating proliferation independently of mitogens.
Conclusions:
- Raf signaling converges with cooperating partners (LT, p53) at the regulation of cyclin/cdk complexes.
- Cellular responses to Raf activation are modulated by p53 status.
- This study reveals a critical interplay between oncogenes and cell cycle regulators in cancer development.