Packham G, Cleveland J L
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Mol Cell Biol. 1994 Sep;14(9):5741-7. doi: 10.1128/mcb.14.9.5741-5747.1994.
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.
c-Myc在细胞周期进程、分化和凋亡的调控中发挥着核心作用。然而，介导c-Myc功能的蛋白质仍有待确定。在白细胞介素-3（IL-3）撤除后，强制表达c-myc会迅速诱导依赖IL-3的32D.3小鼠髓样细胞凋亡，这与鸟氨酸脱羧酶（ODC）的组成型、不依赖生长因子的表达有关，ODC是多胺生物合成的限速酶。在此，我们研究了ODC在c-Myc诱导的凋亡中的作用。与c-myc一样，强制表达ODC足以在IL-3撤除后诱导加速死亡。ODC以剂量依赖的方式诱导细胞死亡，α-二氟甲基鸟氨酸（DFMO）是ODC酶活性的不可逆抑制剂，可有效阻断ODC诱导的细胞死亡。ODC诱导的细胞死亡是由于凋亡的诱导。我们还证明ODC是c-Myc诱导凋亡的介质。源自32D.3的c-myc克隆具有更高水平的ODC酶活性，其死亡速率也是其ODC酶水平的函数。重要的是，用DFMO处理可抑制c-myc克隆的死亡速率。这些发现表明ODC是c-Myc诱导凋亡的重要介质，并提示ODC介导c-Myc的其他功能。
