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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cadherins / metabolism
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Cycle / physiology
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Cells, Cultured
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Cyclin D1 / metabolism
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Cyclin E / metabolism
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / metabolism*
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Endothelial Growth Factors / metabolism
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Epidermal Cells
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Epidermis / metabolism*
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Epidermis / pathology*
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Gene Transfer Techniques
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Genes, Reporter
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Keratinocytes / metabolism
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Lung / pathology
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Lymphokines / metabolism
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Proto-Oncogene Proteins*
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Recombinant Fusion Proteins / metabolism
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
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Telomere / metabolism
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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Cadherins
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Cyclin E
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Endothelial Growth Factors
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Cyclin D1
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CDK4 protein, human
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Cdk4 protein, mouse
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases
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Mitogen-Activated Protein Kinases
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ras Proteins