Cell-cycle progression is not essential for c-Myc to block differentiation

Abstract

The c-myc proto-oncogene has been shown to cause blockages to differentiation in many cell lineages. Although the mechanism by which c-Myc affects this process remains unknown, it is considered that it might result indirectly as an outcome of the continued cell-cycle progression invoked by c-Myc in cells which must growth arrest in order to differentiate. However, as there is little evidence to support this hypothesis, it is equally possible that a differentiation blockage occurs through a mechanism independent of c-Myc's involvement in cell-cycle progression. To explore this possibility we utilised a differentiation-defective variant of the U937 cell line, which still responds to the differentiation inducer by undergoing rapid growth arrest. Analysis of this line during growth arrest revealed that, although the expression of the Myc target gene, ornithine decarboxylase (ODC) was down-regulated, the cells differed from those of the parental line in that they continued to express high levels of c-Myc protein, but did not maintain high levels of expression of the Myc antagonists, mad1 and mxi1. Moreover, antisense down-regulation of the c-Myc protein levels in these growth-arrested cells revealed that this continued c-Myc expression was essential for their differentiation blockage. These data therefore indicate that c-Myc can block differentiation by a mechanism dissociated from its ability to direct cell-cycle progression or the expression of ODC.