State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
Cell Signal. 2013 Jan;25(1):150-8. doi: 10.1016/j.cellsig.2012.09.004. Epub 2012 Sep 7.
JNK signaling functions to induce defense mechanisms that protect organisms against a variety of different situations. The sestrin 2 gene, a p53-regulated member of the sestrins family, which lead to AMPK-dependent inhibition of TOR signaling, emerges as a novel player in autophagy induction. However, the relationship between JNK pathway, autophagy induction and sestrin 2 expression remains elusive. In the present study, we identify JNK as a regulator of autophagy in nasopharyngeal carcinoma cell lines CNE1 and CNE2 exposed to excisanin A or serum deprivation and demonstrate that activation of JNK can cause upregulation of sestrin 2 expression, which could be blocked by specific siRNAs directed against JNK1/2 or c-Jun. Chromatin immunoprecipitation and luciferase reporter analysis revealed that c-Jun was transcriptionally involved in the regulation of sestrin 2. Furthermore, knockdown of sestrin 2 by siRNAs similarly inhibited autophagy induction. Moreover, silencing the expression of autophagy related gene ATG5 or sestrin 2 significantly decreases cell death induced by excisanin A. Our results therefore identify JNK as a novel mediator of sestrin 2 expression, which plays a key role in autophagy induction following anticancer therapies in cancers.
JNK 信号通路的功能是诱导防御机制，使生物体能够抵抗各种不同的情况。Sestrin 2 基因是 sestrins 家族中受 p53 调控的成员之一，它导致 AMPK 依赖性抑制 TOR 信号，是自噬诱导的新成员。然而，JNK 通路、自噬诱导和 sestrin 2 表达之间的关系仍然难以捉摸。在本研究中，我们确定 JNK 是暴露于 excisanin A 或血清剥夺的鼻咽癌细胞系 CNE1 和 CNE2 中自噬的调节剂，并证明 JNK 的激活可导致 sestrin 2 表达的上调，这可被针对 JNK1/2 或 c-Jun 的特异性 siRNA 阻断。染色质免疫沉淀和荧光素酶报告基因分析显示，c-Jun 转录参与 sestrin 2 的调节。此外，siRNAs 下调 sestrin 2 同样抑制自噬诱导。此外，沉默自噬相关基因 ATG5 或 sestrin 2 的表达显著降低 excisanin A 诱导的细胞死亡。因此，我们的研究结果确定了 JNK 作为 sestrin 2 表达的新型介质，它在癌症中抗癌治疗后的自噬诱导中发挥关键作用。
