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 cons istently found to be transcriptionally activated by chromosomal translocati on. 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 establishe d a human EBV-EBNAI 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 ser um. Re-expression of myc activates the cell cycle without inducing apoptosi s. 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-I is expressed in proliferating and arrest ed cells at constant levels. The Cdk inhibitors p16, p21, p27 and p57 are e xpressed at low or not detectable levels in proliferating cells and are not induced after repression of myc. Ectopic expression of p16 inhibits cell c ycle progression. These data suggest that myc triggers proliferation of P49 3-6 cells by promoting the expression of a set of cell cycle activators but not by inactivating cell cycle inhibitors. Int. J. Cancer 87:787-793,2000. (C) 2000 Wiley-Liss, Inc.