Differential apoptotic behaviors of c-myc, N-myc, and L-myc oncoproteins.
c-, N-, and L-myc are related nuclear oncoproteins that bind similar DNA sites and cooperate with activated ras oncogenes to transform primary 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)-dependent 32D hematopoietic cell line. The apoptotic response of each cell line was assessed after IL-3 withdrawal or treatment with four structurally unrelated cytotoxic agents. All three oncoproteins accelerated apoptosis after IL-3 withdrawal. In contrast, whereas c-myc overexpression generally sensitized cells to cytotoxic drugs, N-myc and L-myc overexpression produced resistance. myc expression tended to be associated with a more robust G2-M arrest after drug exposure, but this did not correlate with drug sensitivity or resistance. Bcl-2 and Bcl-X(L) protected control cells against apoptosis after either IL-3 withdrawal or drug exposure, although in some cases this effect could be overridden by myc oncoproteins, particularly N-myc and L-myc. Our results suggest that the apoptotic pathways activated upon IL-3 withdrawal and cytotoxic drug treatment are distinct and differentially affected by members of the myc and Bcl-2 families.
Nesbit
C E
CE
Department of Pediatrics, Children's Hospital of Pittsburgh, Pennsylvania 15213, USA.
Grove
L E
LE
Yin
X
X
Prochownik
E V
EV
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D003470:Culture Media / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007377:Interleukin-3 / Q000172:deficiency; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D051020:bcl-X Protein
D000970:Antineoplastic Agents; D003470:Culture Media; D007377:Interleukin-3; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D051020:bcl-X Protein