DIFFERENTIAL APOPTOTIC BEHAVIORS OF C-MYC, N-MYC, AND L-MYC ONCOPROTEINS

c-,N-, and L-myc are related nuclear oncoproteins that bind similar DN A sites and cooperate with activated ras oncogenes to transform primar y fibroblasts. Although c-myc can also promote apoptosis in some cells after growth factor withdrawal or exposure to cytotoxic agents, roles for N- and L-myc in apoptosis remain undetermined. To address this, c -, N-, or L-myc were stably expressed in the interleukin 3 (IL-3)-depe ndent 32D hematopoietic cell line. The apoptotic response of each cell line was assessed after IL-3 withdrawal or treatment with four struct urally unrelated cytotoxic agents. All three oncoproteins accelerated apoptosis after IL-3 withdrawal. In contrast, whereas c-myc overexpres sion generally sensitized cells to cytotoxic drugs, N-myc and L-myc ov erexpression produced resistance. myc expression tended to be associat ed with a more robust G(2)-M arrest after drug exposure, but this did not correlate with drug sensitivity or resistance. Bcl-2 and Bcl-X-L p rotected control cells against apoptosis after either IL-3 withdrawal or drug exposure, although in some cases this effect could be overridd en by myc oncoproteins, particularly N-myc and L-myc. Our results sugg est that the apoptotic pathways activated upon IL-3 withdrawal and cyt otoxic drug treatment are distinct and differentially affected by memb ers of the myc and Bcl-2 families.