Abstract
MYC transcription factors are potent stimulators of cell proliferation. It has been suggested that the CDK-inhibitor p27kip1 is a critical G1 phase cell cycle target of c-MYC. We show here that mouse embryo fibroblasts deficient for both p27kip1 and the related p21cip1 are still responsive to stimulation by c-MYC and can be arrested in G1 by a dominant negative mutant of c-MYC. This growth arrest can be overruled by ectopic expression of E2F or adenovirus E1A, but not by a mutant of E1A defective for binding to retinoblastoma family proteins. We show that fibroblasts with a genetic disruption of all three retinoblastoma family members (pRb, p107 and p130) are unresponsive to a dominant negative c-MYC mutant. These data indicate that p27kip1 is not the only rate limiting cell cycle target of c-MYC and suggest that regulation of E2F is also essential for c-MYC's mitogenic activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenovirus E1A Proteins / genetics
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Adenovirus E1A Proteins / physiology
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Animals
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Carrier Proteins*
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Cell Cycle / physiology*
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Cell Cycle Proteins*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclins / physiology
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DNA-Binding Proteins*
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E2F Transcription Factors
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Fibroblasts
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G1 Phase / genetics
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G1 Phase / physiology
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Genes, Dominant
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Genes, Retinoblastoma
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Genes, cdc*
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Genes, myc
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / physiology*
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology
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Phosphoproteins / deficiency
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Phosphoproteins / genetics
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Phosphoproteins / physiology
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Proteins*
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Proto-Oncogene Proteins c-myc / physiology*
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Recombinant Fusion Proteins / physiology
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Retinoblastoma Protein / deficiency
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / physiology
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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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S Phase / genetics
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S Phase / physiology
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Transcription Factor DP1
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Transcription Factors / genetics
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Transcription Factors / physiology
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Tumor Suppressor Proteins*
Substances
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Adenovirus E1A Proteins
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Arid4a protein, mouse
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Carrier Proteins
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Cdkn1a protein, mouse
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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E2F Transcription Factors
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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 Proteins c-myc
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Rbl1 protein, mouse
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Rbl2 protein, mouse
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Recombinant Fusion Proteins
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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