Abstract
c-myc is a cellular proto-oncogene associated with a variety of human cancers and is strongly implicated in the control of cellular proliferation, programmed cell death, and differentiation. We have previously reported the first isolation of a c-myc-null cell line. Loss of c-Myc causes a profound growth defect manifested by the lengthening of both the G1 and G2 phases of the cell cycle. To gain a clearer understanding of the role of c-Myc in cellular proliferation, we have performed a comprehensive analysis of the components that regulate cell cycle progression. The largest defect observed in c-myc-/- cells is a 12-fold reduction in the activity of cyclin D1-Cdk4 and -Cdk6 complexes during the G0-to-S transition. Downstream events, such as activation of cyclin E-Cdk2 and cyclin A-Cdk2 complexes, are delayed and reduced in magnitude. However, it is clear that c-Myc affects the cell cycle at multiple independent points, because restoration of the Cdk4 and -6 defect does not significantly increase growth rate. In exponentially cycling cells the absence of c-Myc reduces coordinately the activities of all cyclin-cyclin-dependent kinase complexes. An analysis of cyclin-dependent kinase complex regulators revealed increased expression of p27(KIP1) and decreased expression of Cdk7 in c-myc-/- cells. We propose that c-Myc functions as a crucial link in the coordinate adjustment of growth rate to environmental conditions.
Publication types
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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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Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
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Carrier Proteins*
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Cell Cycle / physiology*
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Cell Cycle Proteins*
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Cell Division
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Cell Line
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Cyclin A / biosynthesis
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Cyclin D
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Cyclin E / biosynthesis
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / biosynthesis
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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 Activation
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Humans
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Microtubule-Associated Proteins / genetics
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases*
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Nuclear Proteins / metabolism
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / metabolism*
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Proteins*
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-fos / biosynthesis
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / physiology*
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Proto-Oncogene Proteins*
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Rats
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Retinoblastoma Protein / metabolism
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Retinoblastoma-Binding Protein 1
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Retinoblastoma-Like Protein p107
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Retinoblastoma-Like Protein p130
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Transcription Factor DP1
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Transcription Factors / biosynthesis
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Tumor Suppressor Proteins*
Substances
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Carrier Proteins
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Cdkn1b protein, rat
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Cell Cycle Proteins
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Cyclin A
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Cyclin D
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Cyclin E
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Cyclins
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DNA-Binding Proteins
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E2F Transcription Factors
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MAS1 protein, human
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Microtubule-Associated Proteins
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Nuclear Proteins
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Phosphoproteins
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Proteins
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-myc
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RBL2 protein, human
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Rbl2 protein, rat
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Retinoblastoma Protein
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Retinoblastoma-Binding Protein 1
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Retinoblastoma-Like Protein p107
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Retinoblastoma-Like Protein p130
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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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Calcium-Calmodulin-Dependent Protein Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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CDK4 protein, human
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CDK6 protein, human
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Cdk2 protein, rat
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Cdk4 protein, rat
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Cdk6 protein, rat
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases