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Identification of CDK4 as a target of c-MYC
H Hermeking1, C Rago, M Schuhmacher
1Howard Hughes Medical Institute, The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, 424 North Bond Street, Baltimore, MD 21231, USA.
Abstract:
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.
Insights
The oncogene c-MYC promotes cell proliferation by regulating gene expression. This study identifies cyclin-dependent kinase 4 (CDK4) as a direct target of c-MYC, linking its oncogenic function to cell-cycle control.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- The oncogene c-MYC is a transcription factor known to drive cell proliferation.
- The precise mechanisms by which c-MYC influences cell-cycle reentry remain incompletely understood.
Purpose of the Study:
- To identify downstream targets of c-MYC that mediate its proliferative effects.
- To elucidate the role of c-MYC in regulating cell-cycle progression.
Main Methods:
- Serial analysis of gene expression (SAGE) was employed to identify c-MYC transcriptional targets.
- Analysis of c-MYC binding sites within the promoter region of candidate genes.
- Assessment of cell-cycle progression and growth defects in c-MYC-deficient cells.
- Complementation studies involving ectopic expression of identified targets.
Main Results:
- The cyclin-dependent kinase 4 (CDK4) gene was identified as a direct transcriptional target of c-MYC.
- c-MYC binding to four conserved sites in the CDK4 promoter rapidly increased CDK4 mRNA levels.
- c-MYC-deficient cells exhibited delayed cell-cycle progression and impaired CDK4 induction.
- Ectopic expression of CDK4 partially rescued the growth defect in c-MYC-deficient cells.
Conclusions:
- CDK4 is a direct transcriptional target of the oncogene c-MYC.
- c-MYC-mediated induction of CDK4 is crucial for promoting cell-cycle reentry and proliferation.
- CDK4 serves as a critical molecular link connecting c-MYC's oncogenic activity to cell-cycle regulation.