Molecular Cancer Research, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.
J Biol Chem. 2013 Jul 26;288(30):21729-41. doi: 10.1074/jbc.M113.463885. Epub 2013 Jun 14.
FOXO (forkhead box O) transcription factors are tumor suppressors and increase the life spans of model organisms. Cellular stress, in particular oxidative stress caused by an increase in levels of reactive oxygen species (ROS), activates FOXOs through JNK-mediated phosphorylation. Importantly, JNK regulation of FOXO is evolutionarily conserved. Here we identified the pathway that mediates ROS-induced JNK-dependent FOXO regulation. Following increased ROS, RALA is activated by the exchange factor RLF (RalGDS-like factor), which is in complex with JIP1 (C-Jun-amino-terminal-interacting protein 1) and JNK. Active RALA consequently regulates assembly and activation of MLK3, MKK4, and JNK onto the JIP1 scaffold. Furthermore, regulation of FOXO by RALA and JIP1 is conserved in C. elegans, where both ral-1 and jip-1 depletion impairs heat shock-induced nuclear translocation of the FOXO orthologue DAF16.
叉头框 O（FOXO）转录因子是肿瘤抑制因子，能延长模式生物的寿命。细胞应激，特别是活性氧（ROS）水平增加引起的氧化应激，通过 JNK 介导的磷酸化激活 FOXO。重要的是，JNK 对 FOXO 的调节在进化上是保守的。在这里，我们确定了介导 ROS 诱导的 JNK 依赖性 FOXO 调节的途径。在 ROS 增加后，RLA 被 RLF（RalGDS 样因子）激活，RLF 与 JIP1（C-Jun-N 末端相互作用蛋白 1）和 JNK 形成复合物。活性 RALA 随后调节 MLK3、MKK4 和 JNK 组装并激活到 JIP1 支架上。此外，RALA 和 JIP1 对 FOXO 的调节在秀丽隐杆线虫中是保守的，在秀丽隐杆线虫中，ral-1 和 jip-1 的耗竭都损害了热休克诱导的 FOXO 同源物 DAF16 的核转位。
