Upregulation of sestrin 2 expression via JNK pathway activation contributes to autophagy induction in cancer cells
Upregulation of sestrin 2 expression via JNK pathway activation contributes to autophagy induction in cancer cells
复制标题
通过 JNK 通路激活上调 sestrin 2 表达有助于诱导癌细胞自噬
DOI：
10.1016/j.cellsig.2012.09.004
复制
发表时间：
2013-01-01
影响因子：
4.8
通讯作者：
Zhu, Xiao-Feng
中科院分区：
文献类型：
--
作者：
Zhang, Xiao-Yue;Wu, Xiao-Qi;Zhu, Xiao-Feng
JNK信号传导具有诱导防御机制的功能，该机制保护生物体免受多种不同情况的影响。sestrin 2基因是sestrins家族中受p53调控的成员，它导致AMPK依赖的TOR信号传导抑制，在自噬诱导中作为一种新的参与者出现。然而，JNK通路、自噬诱导和sestrin 2表达之间的关系仍然不清楚。在本研究中，我们确定JNK是暴露于艾里莫芬烷A或血清剥夺的鼻咽癌细胞系CNE1和CNE2中自噬的调节因子，并证明JNK的激活可导致sestrin 2表达上调，这可被针对JNK1/2或c - Jun的特异性小干扰RNA（siRNAs）阻断。染色质免疫沉淀和荧光素酶报告基因分析显示，c - Jun在转录水平参与sestrin 2的调控。此外，通过siRNAs敲低sestrin 2同样抑制自噬诱导。而且，沉默自噬相关基因ATG5或sestrin 2的表达显著降低由艾里莫芬烷A诱导的细胞死亡。因此，我们的结果确定JNK是sestrin 2表达的一种新型介导因子，它在癌症抗癌治疗后的自噬诱导中起关键作用。（C）2012爱思唯尔公司。保留所有权利。
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. (C) 2012 Elsevier Inc. All rights reserved.