Ras acts with other proteins to induce neoplasia. By itself, however, strong Ras signaling can suppress proliferation of normal cells. In primary epidermal cells, we found that oncogenic Ras transiently decreases cyclin-dependent kinase (CDK) 4 expression in association with cell cycle arrest in G1 phase. CDK4 co-expression circumvents Ras growth suppression and induces invasive human neoplasia resembling squamous cell carcinoma. Tumorigenesis is dependent on CDK4 kinase function, with cyclin D1 required but not sufficient for this process. In facilitating escape from G1 growth restraints, Ras and CDK4 alter the composition of cyclin D and cyclin E complexes and promote resistance to growth inhibition by INK4 cyclin-dependent kinase inhibitors. These data identify a new role for oncogenic Ras in CDK4 regulation and highlight the functional importance of CDK4 suppression in preventing uncontrolled growth.
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We thank A. Oro, J. Crabtree, M. Scott, M. Cleary, P. Jackson, and D. Felsher for presubmission review and helpful discussions. We thank S. Yuspa, E. Fuchs, R. Weinberg, A. Dlugosz, M. Denning, and J. Bickenbach for helpful discussions. For cDNAs, we thank C. Sherr for p18INK4C, p19INK4D, p27KIP1; P. Jackson for p21CIP1; Y. Xiong for CDK6, p15INK4B, p57KIP2; S. Hanks for CDK4; J. Lipsick for cyclin D1; L. Zhu for p16INK4A; D. Hancock and M. McMahon for ERTM. We thank A. Anguiano for assistance with SKY-FISH. We also thank N. Griffiths and P. Bernstein for expert administrative support. This work was supported by the USVA Office of Research and Development and by NIH AR45192 and AR43799 (to P.A.K.).
The authors declare no competing financial interests.
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