c-Myc blazing a trail of death - Coupling of the mitochondrial and death receptor apoptosis pathways by c-Myc
c-Myc blazing a trail of death - Coupling of the mitochondrial and death receptor apoptosis pathways by c-Myc
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DOI：
10.4161/cc.6.20.4917
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发表时间：
2007-10-15
期刊：
影响因子：
4.3
通讯作者：
Klefstrom, Juha
中科院分区：
文献类型：
--
作者：
Nieminen, Anni I.;Partanen, Johanna I.;Klefstrom, Juha
TRAIL配体通过与两种死亡受体（DR 4和DR 5）结合，选择性地诱导肿瘤细胞凋亡，有望成为一种潜在的抗肿瘤治疗剂。虽然人们早就知道TRAIL受体通常在各种正常组织中表达，但人们还不清楚为什么TRAIL杀死肿瘤细胞而不伤害正常细胞。原型癌基因c-Myc促进细胞周期，同时引发Bcl-2家族控制的线粒体凋亡途径的激活。c-Myc依赖性凋亡敏化的显著反映是c-Myc诱导的细胞对TRAIL和其他死亡受体配体的显著脆弱性。本文综述了TRAIL/TRAIL受体系统的死亡机制以及c-Myc与线粒体凋亡途径的关系，重点介绍了我们通过巴克将c-Myc与TRAIL死亡受体途径偶联的研究工作。最后，我们提出了一个新的启动模型来解释c-Myc-巴克相互作用如何放大TRAIL诱导的caspase 8-Bid途径，以诱导全面的凋亡。我们讨论了这些发现的影响，了解选择性细胞毒性的TRAIL和死亡受体途径的治疗开发。
TRAIL ligand induces selectively apoptosis in tumor cells by binding to two death receptors (DR4 and DR5) and holds promise as a potential therapeutic agent against cancer. While it has been known for long time that TRAIL receptors are commonly expressed in wide variety of normal tissues, it is not well understood why TRAIL kills tumor cells but leaves normal cells unharmed. The prototypic oncogene c-Myc promotes the cell cycle and simultaneously primes activation of the Bcl-2 family controlled mitochondria apoptosis pathway. A striking reflection of the c-Myc-dependent apoptotic sensitization is the dramatic c-Myc-induced vulnerability of cells to TRAIL and other death receptor ligands. Here we summarize the recent findings regarding the death mechanisms of TRAIL/TRAIL receptor system and the connection of c-Myc to the mitochondrial apoptosis pathway, focusing on our work that couples c-Myc via Bak to the TRAIL death receptor pathway. Finally, we present a mitochondria-priming model to explain how c-Myc-Bak interaction amplifies the TRAIL-induced caspase 8-Bid pathway to induce full-blown apoptosis. We discuss the implications of these findings for understanding the selective cytotoxicity of TRAIL and for the therapeutic exploitation of the death receptor pathway.