Abstract
Numerous experiments have defined a critical role for the G1 cyclins and associated kinases in allowing a normal progression of cells from a quiescent state, through G1, and into S phase. We now demonstrate that G1 cyclin-dependent kinase activity is critical for the accumulation of E2F activity late in G1. Moreover, E2F-1 overexpression can overcome a G1 arrest caused by the inhibition of G1 cyclin-dependent kinase activity, consistent with E2F activation being an important consequence of the action of G1 cyclins. E2F-1 also overcomes a G1 block caused by gamma irradiation and leads to an apparent complete replication of the cellular genome and entry into mitosis. This E2F-1-mediated induction of S phase and mitosis is not accompanied by the rise in either cyclin D-associated kinase activity or cdk2 activity that is normally observed during the G1 phase of the cell cycle. We conclude that one key function for G1 cyclin-dependent kinase activity is the activation of E2F-1, that the accumulation of E2F activity may be sufficient to allow initiation and completion of S phase, but that additional events, including G1 cyclin kinase activity, are likely necessary for a normal proliferative event.
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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Blotting, Western
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CDC2-CDC28 Kinases*
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Carrier Proteins / genetics
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Carrier Proteins / pharmacology
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Cell Cycle Proteins*
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / genetics
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DNA / radiation effects
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DNA-Binding Proteins*
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E2F Transcription Factors
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E2F1 Transcription Factor
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G1 Phase* / radiation effects
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G2 Phase
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Gamma Rays
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Gene Expression Regulation
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / pharmacology
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Mitosis
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Plasmids
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases / genetics
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Retinoblastoma Protein / biosynthesis
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Retinoblastoma Protein / genetics
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Retinoblastoma-Binding Protein 1
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S Phase
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcription Factors / radiation effects
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Tumor Suppressor Proteins*
Substances
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Carrier Proteins
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p16
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DNA-Binding Proteins
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E2F Transcription Factors
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E2F1 Transcription Factor
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Microtubule-Associated Proteins
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Retinoblastoma Protein
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Retinoblastoma-Binding Protein 1
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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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DNA
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases