p27kip1-independent cell cycle regulation by MYC.
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.
Berns
K
K
Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands' Cancer Institute, Amsterdam.
Martins
C
C
Dannenberg
J H
JH
Berns
A
A
te Riele
H
H
Bernards
R
R
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000502:physiology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005347:Fibroblasts; D016193:G1 Phase / Q000235:genetics / Q000502:physiology; D005799:Genes, Dominant; D016161:Genes, Retinoblastoma; D018816:Genes, cdc; D016259:Genes, myc; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D056465:Retinoblastoma-Binding Protein 1; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D016196:S Phase / Q000235:genetics / Q000502:physiology; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins
D017500:Adenovirus E1A Proteins; C533431:Arid4a protein, mouse; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D050680:Transcription Factor DP1; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27