Bax is a transcriptional target and mediator of c-Myc-induced apoptosis

The c-Myc oncoprotein is a transcription factor involved in cellular transf ormation as well as apoptotic cell death. We show here that overexpression of c-Myc delivered by an adenovirus vector up-regulates endogenous proapopt otic bar mRNA and protein expression in human cells. In contrast, the cytot oxic tumor necrosis factor-related apoptosis-inducing ligand induces cell d eath without up-regulating bar expression. c-Myc/Max heterodimers bind to c anonical E-box elements located in the bar promoter region as demonstrated by electrophoretic mobility shift analysis and DNaseI foot-printing assays, Analysis of bar regulatory region mutants suggests a model involving myc-d ependent activation as well as relief of repression through distinct E-box elements. c-Myc-null cells are deficient in bar-promoter activation as comp ared with wild-type c-Myc-expressing cells. Overexpression of c-Myc in seru m-starved human or mouse embryonic cells leads to apoptosis which is signif icantly reduced in the presence of growth factor-containing serum. c-Myc-in duced apoptosis appears to be deficient in bar-null as compared with bar-wi ld-type mouse embryonic fibroblasts, The results suggest that the cell deat h-promoting gene bar is directly downstream of c-Myc in a pathway leading t o apoptosis.