Identification of CDK4 as a target of c-MYC.
The prototypic oncogene c-MYC encodes a transcription factor that can drive proliferation by promoting cell-cycle reentry. However, the mechanisms through which c-MYC achieves these effects have been unclear. Using serial analysis of gene expression, we have identified the cyclin-dependent kinase 4 (CDK4) gene as a transcriptional target of c-MYC. c-MYC induced a rapid increase in CDK4 mRNA levels through four highly conserved c-MYC binding sites within the CDK4 promoter. Cell-cycle progression is delayed in c-MYC-deficient RAT1 cells, and this delay was associated with a defect in CDK4 induction. Ectopic expression of CDK4 in these cells partially alleviated the growth defect. Thus, CDK4 provides a direct link between the oncogenic effects of c-MYC and cell-cycle regulation.
Hermeking
H
H
Howard Hughes Medical Institute, The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, 424 North Bond Street, Baltimore, MD 21231, USA.
Rago
C
C
Schuhmacher
M
M
Li
Q
Q
Barrett
J F
JF
Obaya
A J
AJ
O'Connell
B C
BC
Mateyak
M K
MK
Tam
W
W
Kohlhuber
F
F
Dang
C V
CV
Sedivy
J M
JM
Eick
D
D
Vogelstein
B
B
Kinzler
K W
KW
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D018076:DNA, Complementary; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases