State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
Life Sciences Institute and College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Oncogene. 2014 Mar 27;33(13):1629-39. doi: 10.1038/onc.2013.116. Epub 2013 Apr 15.
The orphan nuclear receptor Nur77 regulates diverse cellular activities, including cell proliferation, differentiation and apoptosis. The c-Jun N-terminal kinase (JNK) have a dual role in controlling the function of Nur77. While JNK-mediated phosphorylation of Nur77 positively regulates its translocation to the mitochondria to induce apoptosis, it negatively regulates the stability of Nur77. The underlying mechanism for the dual role of JNK in regulating Nur77, however, is unclear. Here, we report that E3 ubiquitin ligase Smad ubiquitination regulatory factor 1 (Smurf1) prevents Nur77 degradation through mediating its unconventional ubiquitination, thereby mitigating the JNK-mediated downregulating effect, which leads to Nur77 accumulation and subsequent translocation to mitochondria to trigger apoptosis. In this process, protein kinase A (PKA)-mediated phosphorylation of Smurf1 at Thr306 is a prerequisite step. Accordingly, cyclic AMP/PKA signaling switches the fate of Nur77 from degradation to triggering apoptosis in chemotherapy drug cisplatin-treated cells. Hence, our study revealed a novel mechanism, by which PKA/Smurf1 antagonizes the downregulating effect of JNK on Nur77, leading to the accumulation of Nur77 for apoptosis induction triggered by cisplatin.
孤儿核受体 Nur77 调节多种细胞活动，包括细胞增殖、分化和凋亡。c-Jun N 端激酶（JNK）在控制 Nur77 功能方面具有双重作用。虽然 JNK 介导的 Nur77 磷酸化正向调节其向线粒体的易位以诱导细胞凋亡，但它负向调节 Nur77 的稳定性。然而，JNK 调节 Nur77 的双重作用的潜在机制尚不清楚。在这里，我们报告 E3 泛素连接酶 Smad 泛素化调节因子 1（Smurf1）通过介导其非典型泛素化来防止 Nur77 降解，从而减轻 JNK 介导的下调作用，导致 Nur77 积累并随后易位到线粒体引发细胞凋亡。在这个过程中，蛋白激酶 A（PKA）介导的 Smurf1 的 Thr306 磷酸化是一个前提步骤。因此，环 AMP/PKA 信号转导将 Nur77 的命运从降解切换为顺铂处理的细胞中触发细胞凋亡。因此，我们的研究揭示了一种新的机制，即 PKA/Smurf1 拮抗 JNK 对 Nur77 的下调作用，导致 Nur77 积累，从而引发顺铂诱导的细胞凋亡。
