Previous studies in human myeloid leukemia cells (HL-60, U-937, THP-1) suggested an involvement of the c-myc gene in the control of mutually exclusive pathways, such as retrodifferentiation and cell death. Treatment of U-937 cells with 12-O-tetradecanoyl phorbol-13-acetate (TPA) which is associated with the induction of a monocytic differentiation program and growth arrest, revealed an initial up-regulation of c-myc, c-max, and mxi1 mRNAs after 1-6 h. Thereafter expression of these genes significantly declined to barely detectable levels when the cells ceased to grow after 12-24 h of TPA treatment. Between 7 and 11 days of TPA-induced G0/G1 cell cycle arrest, expression of the c-max and mxi1 genes continuously increased up to 8-fold until 32 days and declined to control levels when the cells regained proliferative capacity by 36 days. In contrast, c-myc mRNAs remained down-regulated during periods of growth arrest and increased only during re-entry into the cell cycle after 36 days. This effect is consistent with a retrodifferentiation process, whereby previously differentiated cells revert back to the undifferentiated phenotype and re-enter the cell cycle. Different results were obtained during serum starvation-induced cell death of U-937 cells. After 48-72 h of serum-starvation, expression of the c-myc and c-max genes were significantly down-regulated by 4-fold and 3-fold, respectively, while there was little, if any, change in mxi1 mRNA levels. Analysis of cell death in serum-starved U-937 cells demonstrated progressively increasing DNA fragmentation reaching 45.4% +/- 0.9% after 72 h. Synchronization of proliferating U-937 cells throughout distinct phases of the cell cycle exhibited little, if any, change in c-myc, c-max and mxi1 mRNAs. Furthermore, like c-myc, c-max and mxi1 mRNA transcripts appeared to be regulated primarily by post-transcriptional mechanisms, and c-max and mxi1 half-lives exceeded 4 h in contrast to < 60 min for the c-myc gene. Taken together, these findings suggested differential regulation and inverse expression levels of c-myc compared to c-max and mxi1 during differentiation, retrodifferentiation and cell death.