Abstract
Considerable evidence points to a role for G1 cyclin-dependent kinase (CDK) in allowing the accumulation of E2F transcription factor activity and induction of the S phase of the cell cycle. Numerous experiments have also demonstrated a critical role for both Myc and Ras activities in allowing cell-cycle progression. Here we show that inhibition of Ras activity blocks the normal growth-dependent activation of G1 CDK, prevents activation of the target genes of E2F, and results in cell-cycle arrest in G1. We also show that Ras is essential for entry into the S phase in Rb+/+ fibroblasts but not in Rb-/- fibroblasts, establishing a link between Ras and the G1 CDK/Rb/E2F pathway. However, although expression of Ras alone will not induce G1 CDK activity or S phase, coexpression of Ras with Myc allows the generation of cyclin E-dependent kinase activity and the induction of S phase, coincident with the loss of the p27 cyclin-dependent kinase inhibitor (CKI). These results suggest that Ras, along with the activation of additional pathways, is required for the generation of G1 CDK activity, and that activation of cyclin E-dependent kinase in particular depends on the cooperative action of Ras and Myc.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CDC2-CDC28 Kinases*
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Carrier Proteins*
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Cell Cycle Proteins*
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Cell Line
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / metabolism*
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Cyclins / metabolism*
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DNA-Binding Proteins*
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E2F Transcription Factors
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Enzyme Inhibitors / metabolism
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G1 Phase
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Mice
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Microtubule-Associated Proteins / metabolism
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Mutation
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins c-myc / physiology*
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism
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Retinoblastoma-Binding Protein 1
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S Phase
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Transcription Factor DP1
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Transcription Factors
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Tumor Suppressor Proteins*
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ras Proteins / antagonists & inhibitors
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ras Proteins / genetics
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ras Proteins / physiology*
Substances
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Arid4a protein, mouse
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Carrier Proteins
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cyclins
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DNA-Binding Proteins
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E2F Transcription Factors
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Enzyme Inhibitors
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Microtubule-Associated Proteins
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Proto-Oncogene Proteins c-myc
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Retinoblastoma Protein
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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Cdk2 protein, mouse
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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ras Proteins