CELL-CYCLE PROGRESSION IS NOT ESSENTIAL FOR C-MYC TO BLOCK DIFFERENTIATION

The c-myc proto-oncogene has been shown to cause blockages to differen tiation in many cell lineages, Although the mechanism by which c-Myc a ffects this process remains unknown, it is considered that it might re sult indirectly as an outcome of the continued cell-cycle progression invoked by c-Myc in cells which must growth arrest in order to differe ntiate, However, as there is little evidence to support this hypothesi s, it is equally possible that a differentiation blockage occurs throu gh a mechanism independent of c-Myc's involvement in cell-cycle progre ssion, To explore this possibility me utilised a differentiation-defec tive variant of the U937 cell line, which still responds to the differ entiation inducer by undergoing rapid growth Analysis of this line dur ing growth arrest revealed that, although the expression of the Myc ta rget gene, ornithine decarboxylase (ODC) was down-regulated, the cells differed from those of the parental line in that they continued to ex press high levels of c-Myc protein, did not but maintain levels of exp ression of the Myc antagonists, mad1 and mxi1. Moreover, antisense dow n-regulation of the c-Myc protein levels in these growth-arrested cell s revealed that this continued c-Myc expression was essential for thei r differentiation blockage, These data therefore indicate that c-Myc c an block differentiation by a mechanism dissociated from its ability t o direct cell-cycle progression or the expression of ODC.