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CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis

Nature Medicine volume 8, pages 1105–1114 (2002)Cite this article

Abstract

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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Figure 1: Ras effects on regulators of the G1/S transition.
Figure 2: Epithelial growth inhibition by active Ras is bypassed by CDK4 co-expression.
Figure 3: Characterization of Ras-CDK4 neoplasia.
Figure 4: CDK4 kinase function, telomere studies, and proliferative cell output.
Figure 5: Model of Ras-CDK4 induction of growth and neoplasia.

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Acknowledgements

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.).

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  1. Mirella Lazarov and Yoshiaki Kubo: M.L. and Y.K. contributed equally to this study.

Authors and Affiliations

  1. VAPalo Alto Healthcare System, Palo Alto, California, USA

    Mirella Lazarov, Yoshiaki Kubo, Ti Cai, Maya Dajee, Masahito Tarutani, Qun Lin, Min Fang, Shiying Tao, Cheryl L. Green & Paul A. Khavari

  2. the Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA

    Mirella Lazarov, Yoshiaki Kubo, Ti Cai, Maya Dajee, Masahito Tarutani, Qun Lin, Min Fang, Shiying Tao, Cheryl L. Green & Paul A. Khavari

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Lazarov, M., Kubo, Y., Cai, T. et al. CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nat Med 8, 1105–1114 (2002). https://doi.org/10.1038/nm779

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