Control of cell growth by c-Myc in the absence of cell division

Abstract

The c-Myc protein (Myc) is a transcription factor, and deregulated expression of the c-myc gene (myc) is frequently found in tumours. In Burkitt's lymphoma (BL), myc is transcriptionally activated by chromosomal translocation. We have used a B-cell line called P493-6 that carries a conditional myc allele to elucidate the role of Myc in the proliferation of BL cells. Regulation of proliferation involves the coordination of cell growth (accumulation of cell mass) and cell division [1] [2] [3]. Here, we show that division of P493-6 cells was strictly dependent on the expression of the conditional myc allele and the presence of foetal calf serum (FCS). More importantly, cell growth was regulated by Myc without FCS: Myc alone induced an increase in cell size and positively regulated protein synthesis. An increase in protein synthesis is thought to be one of the causes of cell mass increase. Furthermore, Myc stimulated metabolic activities, as indicated by the acidification of culture medium and the activation of mitochondrial enzymes. Our results confirm the model that Myc is involved in the regulation of cell growth [4] and provide, for the first time, direct evidence that Myc induces cell growth, that is, an increase in cell size, uncoupled from cell division.

Epstein–Barr virus promotes genomic instability in Burkitt's lymphoma

“…To this end, presence of gH2AX was investigated in the P493-6 cell line that carries a recombinant EBV with an estrogen-driven EBNA2 and a conditional c-myc gene (Schuhmacher et al, 1999). In the presence of estrogen and tetracycline, the growth of P493-6 cells is driven by a latency III gene expression program (P493-LCL), whereas withdrawal of the drugs results in switch to latency I-like BL phenotype with high expression of c-myc (P493-BL).…”

“…EBV gene expression was confirmed by Western blot using specific polyclonal and monoclonal antibodies (not shown). Switch between BL-and LCL-like phenotypes was induced in the P493-6 cell line (Schuhmacher et al, 1999) by culture in medium supplemented with 0.5 mg/ml tetracycline and 1 mM of b-estradiol, which resulted in upregulation of LMP1 and downregulation of c-Myc below detection levels.…”

Normal and c-Myc-promoted human keratinocyte differentiation both occur via a novel cell cycle involving cellular growth and endoreplication

“…Interestingly, the phenotype caused by a 48 h nocodazole treatment was very similar to that observed after activation of c-Myc for 5 days (Figure 6d,f; Gandarillas and Watt, 1997). Four very recent reports, together with our results, suggest that continuous activity of c-Myc may uncouple cell growth and cell division: (a) overexpression of c-Myc promoted endoreplication in ®broblasts and epithelial cells that were arrested in metaphase (Li and Dang, 1999); (b) dmyc, the drosophila homologue of c-Myc, stimulated cellular growth rather than proliferation, due to mitosis being independently controlled (Johnston et al, 1999) and (c) continuous c-Myc activity provoked an increase in protein synthesis and cell size in a B-cell line and during lymphocyte development of transgenic mice when stimulating cell growth but not cell division (Iritani and Eisenman, 1999;Schuhmacher et al, 1999).…”

“…By driving cellular growth and cell cycle progression, c-Myc may promote proliferation when mitosis is correctly executed, but di erentiation and endoreplication when mitosis is impaired (see also Iritani and Eissenman, 1999;Schuhmacher et al, 1999). It is worth noting that c-Myc activity caused both polyploidy and apoptosis in Rat-1 cells in the absence of mitosis (Li and Dang, 1999), and that terminal di erentiation in keratinocytes may be the counterpart of apoptosis in other cell types (reviewed in Gandarillas, 2000).…”

Antagonistic effects ofc-myc and Epstein-Barr virus latent genes on the phenotype of human B cells

“…To better understand the role of c-myc and EBNA2 and its targets for the phenotypic shifts observed, we have developed the cell line P493-6 in which EBNA2 and c-myc can be regulated independently of each other. This cell line has been generated by introducing a tetracycline-regulatable c-myc gene into EREB2-5 cells 16,17 using an episomal vector carrying the gene coding for the tetracycline repressor-VP16 transactivator fusion protein 18 and on the same molecule the c-myc gene under the control of a tetracycline regulated promoter. The cells can proliferate either on an EBV driven program (in the presence of estrogen and tetracycline) or proliferate in a c-myc driven fashion when estrogen and tetracycline are withdrawn.…”