Ornithine decarboxylase is a mediator of c-Myc-induced apoptosis.
c-Myc plays a central role in the regulation of cell cycle progression, differentiation, and apoptosis. However, the proteins which mediate c-Myc function(s) remain to be determined. Enforced c-myc expression rapidly induces apoptosis in interleukin-3 (IL-3)-dependent 32D.3 murine myeloid cells following IL-3 withdrawal, and this is associated with the constitutive, growth factor-independent expression of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis. Here we have examined the role of ODC in c-Myc-induced apoptosis. Enforced expression of ODC, like c-myc, is sufficient to induce accelerated death following IL-3 withdrawal. ODC induced cell death in a dose-dependent fashion, and alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzyme activity, effectively blocked ODC-induced cell death. ODC-induced cell death was due to the induction of apoptosis. We also demonstrate that ODC is a mediator of c-Myc-induced apoptosis. 32D.3-derived c-myc clones have augmented levels of ODC enzyme activity, and their rates of death were also a function of their ODC enzyme levels. Importantly, the rates of death of c-myc clones were inhibited by treatment with DFMO. These findings demonstrate that ODC is an important mediator of c-Myc-induced apoptosis and suggest that ODC mediates other c-Myc functions.
Packham
G
G
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Cleveland
J L
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D000518:Eflornithine / Q000494:pharmacology; D015870:Gene Expression; D016259:Genes, myc; D066298:In Vitro Techniques; D007377:Interleukin-3 / Q000502:physiology; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology
D007377:Interleukin-3; D016271:Proto-Oncogene Proteins c-myc; D009955:Ornithine Decarboxylase; D000518:Eflornithine