JNK signaling in neomycin-induced vestibular hair cell death
JNK signaling in neomycin-induced vestibular hair cell death
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DOI：
10.1016/j.heares.2006.08.009
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发表时间：
2006-11-01
期刊：
影响因子：
2.8
通讯作者：
Cunningham, Lisa L.
中科院分区：
文献类型：
--
作者：
Sugahara, Kazuma;Rubel, Edwin W.;Cunningham, Lisa L.
机械感觉毛细胞对暴露于耳毒性药物（包括氨基糖苷类抗生素）的凋亡反应敏感。c-Jun N-末端激酶（JNK）是一种应激激活的蛋白激酶，其可以在多种系统中促进凋亡性细胞死亡。抑制JNK信号通路可以防止氨基糖苷类药物诱导的耳蜗和前庭感觉毛细胞死亡。我们用体外制备的成年小鼠椭圆囊来研究JNK激活在氨基糖苷类药物诱导的毛细胞死亡中的作用。CEP-11004用作JNK信号传导的间接抑制剂。免疫组化显示，JNK及其下游靶点c-Jun在暴露于新霉素的椭圆囊毛细胞中磷酸化。CEP-11004抑制新霉素诱导的JNK和c-Jun的磷酸化。CEP-11004抑制暴露于中等剂量新霉素的椭圆囊中的毛细胞死亡。然而，在剂量-反应函数中，结果并不一致; CEP-11004不能抑制暴露于高剂量新霉素的椭圆囊中的毛细胞死亡。CEP-11004诱导的保护作用不是由于PKC或p38的抑制，因为白屈菜红碱和SB 203580都不能模拟CEP-11004的保护作用。此外，抑制JNK抑制了毛细胞中caspase-9的活化。这些结果表明JNK在新霉素诱导的前庭毛细胞死亡和caspase-9激活中起重要作用。(c)2006 Elsevier B. V.保留所有权利。
Mechanosensory hair cells are susceptible to apoptotic death in response to exposure to ototoxic drugs, including aminoglycoside antibiotics. The c-Jun n-terminal kinase (JNK) is a stress-activated protein kinase that can promote apoptotic cell death in a variety of systems. Inhibition of the JNK signaling pathway can prevent aminoglycoside-induced death of cochlear and vestibular sensory hair cells. We used an in vitro preparation of utricles from adult mice to examine the role of JNK activation in aminoglycoside-induced hair cell death. CEP-11004 was used as an indirect inhibitor of JNK signaling. Immunohistochemistry showed that both JNK and its downstream target c-Jun are phosphorylated in hair cells of utricles exposed to neomycin. CEP-11004 inhibited neomycin-induced phosphorylation of both JNK and c-Jun. CEP-11004 inhibited hair cell death in utricles exposed to moderate doses of neomycin. However, the results were not uniform across the dose-response function; CEP-11004 did not inhibit hair cell death in utricles exposed to high-dose neomycin. The CEP-11004-induced protective effect was not due to inhibition of PKC or p38, since neither Chelerythrine nor SB203580 could mimic the protective effect of CEP-11004. In addition, inhibition of JNK inhibited the activation of caspase-9 in hair cells. These results indicate that JNK plays an important role in neomycin-induced vestibular hair cell death and caspase-9 activation. (c) 2006 Elsevier B.V. All rights reserved.