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Laboratory of Molecular Oncology and Cell Cycle Regulation [K. O. M., M. S. R., D. T. D., Z. J., W. S. E-D.], Howard Hughes Medical Institute [W. S. E-D.], Departments of Medicine [M. S. R., D. T. D., W. S. E-D.], Genetics [W. S. E-D.], and Pharmacology [W. S. E-D.], University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6148; National Children’s Medical Research Center, Tokyo, Japan 154 [T. M.]; and The Burnham Institute, La Jolla, California 92037 [J. C. R.]
The c-Myc oncoprotein is a transcription factor involved in cellular transformation as well as apoptotic cell death. We show here that overexpression of c-Myc delivered by an adenovirus vector up-regulates endogenous proapoptotic bax mRNA and protein expression in human cells. In contrast, the cytotoxic tumor necrosis factor-related apoptosis-inducing ligand induces cell death without up-regulating bax expression. c-Myc/Max heterodimers bind to canonical E-box elements located in the bax promoter region as demonstrated by electrophoretic mobility shift analysis and DNaseI foot-printing assays. Analysis of bax regulatory region mutants suggests a model involving myc-dependent activation as well as relief of repression through distinct E-box elements. c-Myc-null cells are deficient in bax-promoter activation as compared with wild-type c-Myc-expressing cells. Overexpression of c-Myc in serum-starved human or mouse embryonic cells leads to apoptosis which is significantly reduced in the presence of growth factor-containing serum. c-Myc-induced apoptosis appears to be deficient in bax-null as compared with bax-wild-type mouse embryonic fibroblasts. The results suggest that the cell death-promoting gene bax is directly downstream of c-Myc in a pathway leading to apoptosis.
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