You Zongbing, Madrid Lee V, Saims Daniel, Sedivy John, Wang Cun-Yu
Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA.
J Biol Chem. 2002 Sep 27;277(39):36671-7. doi: 10.1074/jbc.M203213200. Epub 2002 Jul 30.
Nuclear factor kappaB (NF-kappaB) plays a key role in suppression of tumor necrosis factor (TNF)-mediated apoptosis by inducing a variety of anti-apoptotic genes. Expression of c-Myc has been shown to sensitize cells to TNF-mediated apoptosis by inhibiting NF-kappaB activation. However, the precise step in the NF-kappaB signaling pathway and apoptosis modified by c-Myc has not been identified. Using the inducible c-MycER system and c-Myc null fibroblasts, we found that expression of c-Myc inhibited NF-kappaB activation by interfering with RelA/p65 transactivation but not nuclear translocation of NF-kappaB. Activation of c-Myc promoted TNF-induced release of cytochrome c from mitochondria to the cytosol because of the inhibition of NF-kappaB. Furthermore, we found that NF-kappaB-inducible gene A1 was attenuated by expression of c-Myc and that the restoration of A1 expression suppressed c-Myc-induced TNF sensitization. Our results elucidate the molecular mechanisms by which c-Myc increases cell susceptibility to TNF-mediated apoptosis, indicating that c-Myc may exhibit its pro-apoptotic activities by repression of cell survival genes.
核因子κB（NF-κB）通过诱导多种抗凋亡基因，在抑制肿瘤坏死因子（TNF）介导的细胞凋亡中起关键作用。c-Myc的表达已被证明可通过抑制NF-κB激活使细胞对TNF介导的细胞凋亡敏感。然而，c-Myc修饰的NF-κB信号通路和细胞凋亡的确切步骤尚未确定。使用可诱导的c-MycER系统和c-Myc基因缺失的成纤维细胞，我们发现c-Myc的表达通过干扰RelA/p65反式激活而不是NF-κB的核转位来抑制NF-κB激活。由于NF-κB受到抑制，c-Myc的激活促进了TNF诱导的细胞色素c从线粒体释放到细胞质中。此外，我们发现NF-κB诱导基因A1的表达因c-Myc的表达而减弱，并且A1表达的恢复抑制了c-Myc诱导的TNF敏感性。我们的结果阐明了c-Myc增加细胞对TNF介导的细胞凋亡敏感性的分子机制，表明c-Myc可能通过抑制细胞存活基因来发挥其促凋亡活性。
