Cell cycle activation by c-myc in a burkitt lymphoma model cell line.
The product of the proto-oncogene c-myc (myc) is a potent activator of cell proliferation. In Burkitt lymphoma (BL), a human B-cell tumor, myc is consistently found to be transcriptionally activated by chromosomal translocation. The mechanisms by which myc promotes cell cycle progression in B-cells is not known. As a model for myc activation in BL cells, we have established a human EBV-EBNA1 positive B-cell line, P493-6, in which myc is expressed under the control of a tetracycline regulated promoter. If the expression of myc is switched off, P493-6 cells arrest in G0/G1 in the presence of serum. Re-expression of myc activates the cell cycle without inducing apoptosis. myc triggers the expression of cyclin D2, cyclin E and Cdk4, followed by the activation of cyclin E-associated kinase and hyper-phosphorylation of Rb. The transcription factor E2F-1 is expressed in proliferating and arrested cells at constant levels. The Cdk inhibitors p16, p21, p27 and p57 are expressed at low or not detectable levels in proliferating cells and are not induced after repression of myc. Ectopic expression of p16 inhibits cell cycle progression. These data suggest that myc triggers proliferation of P493-6 cells by promoting the expression of a set of cell cycle activators but not by inactivating cell cycle inhibitors.
Pajic
A
A
Institute for Clinical Molecular Biology and Tumor Genetics, GSF-Research Center for Environment and Health, Munich, Germany.
Spitkovsky
D
D
Christoph
B
B
Kempkes
B
B
Schuhmacher
M
M
Staege
M S
MS
Brielmeier
M
M
Ellwart
J
J
Kohlhuber
F
F
Bornkamm
G W
GW
Polack
A
A
Eick
D
D
D002051:Burkitt Lymphoma / Q000378:metabolism / Q000503:physiopathology*; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107; D013752:Tetracycline / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D013752:Tetracycline