c-Myb protects cochlear hair cells from cisplatin-induced damage via the PI3K/Akt signaling pathway.
c-Myb protects cochlear hair cells from cisplatin-induced damage via the PI3K/Akt signaling pathway.
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DOI：
10.1038/s41420-022-00879-9
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发表时间：
2022-02-24
影响因子：
7
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Bu C;Xu L;Han Y;Wang M;Wang X;Liu W;Chai R;Wang H
转录因子 c-Myb 对于细胞存活、增殖、分化和凋亡至关重要。我们之前曾报道过 c-Myb 敲低会加剧新霉素诱导的耳蜗细胞损伤。然而，c-Myb 在哺乳动物内耳中的功能和调节仍不清楚。在这里，我们首先发现在体内顺铂损伤后，耳蜗HC中c-Myb的表达下调。接下来，为了研究c-Myb在顺铂处理的HC中的作用，构建了过表达c-Myb的重组病毒AAV-ie-CAG-Myb-HA（AAV-c-Myb）并转染到HC中。转染病毒后，培养的耳蜗HC中c-Myb的蛋白表达有效上调，从而增加了顺铂体外损伤后耳蜗HC的活力，减少了HC的凋亡，并降低了细胞内活性氧（ROS）水平。体内AAV-c-Myb转染后HC中c-Myb的过表达也促进了HC的存活，改善了小鼠的听力功能，并减少了顺铂损伤后HC的凋亡。此外，生成了c-Myb-HC条件敲除小鼠（Prestin；c-Myb-cKO），其中c-Myb表达仅在耳蜗OHC中下调，并且顺铂诱导的HC损失、细胞凋亡和听力缺陷在Prestin中均加剧； c-Myb-cKO 小鼠体内用顺铂治疗。最后，机制研究表明，c-Myb 对 PI3K/Akt 信号通路的上调有助于体外顺铂暴露后 HC 存活率的增加。这项工作的结果表明，c-Myb 可能作为预防顺铂引起的 HC 损伤和听力损失的新靶点。
The transcription factor c-Myb is vital for cell survival, proliferation, differentiation, and apoptosis. We have previously reported that c-Myb knockdown exacerbates neomycin-induced damage to cochlea cells. However, the function and regulation of c-Myb in the mammalian inner ear remains unclear. Here, we first found that the expression of c-Myb in cochlear HCs was downregulated after cisplatin damage in vivo. Next, to investigate the role of c-Myb in HCs treated with cisplatin, the recombinant virus AAV-ie-CAG-Myb-HA (AAV-c-Myb) that overexpresses c-Myb was constructed and transfected into HCs. The protein expression of c-Myb was effectively up-regulated in cultured cochlear HCs after the virus transfection, which increased cochlear HC viability, decreased HC apoptosis and reduced intracellular reactive oxygen species (ROS) levels after cisplatin injury in vitro. The overexpression of c-Myb in HCs after AAV-c-Myb transfection in vivo also promoted HC survival, improved the hearing function of mice and reduced HC apoptosis after cisplatin injury. Furthermore, c-Myb-HC conditional knockout mice (Prestin; c-Myb-cKO) in which c-Myb expression is downregulated only in cochlear OHCs were generated and the cisplatin-induced HCs loss, apoptosis and hearing deficit were all exacerbated in Prestin; c-Myb-cKO mice treated with cisplatin in vivo. Finally, mechanistic studies showed that upregulation of the PI3K/Akt signaling pathway by c-Myb contributed to the increased HC survival after cisplatin exposure in vitro. The findings from this work suggest that c-Myb might serve as a new target for the prevention of cisplatin-induced HC damage and hearing loss.
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影响因子：
1.5
作者：
Fang, Jie;Zhang, Wen-Cheng;Yamashita, Tetsuji;Gao, Jiangang;Zhu, Min-Sheng;Zuo, Jian
通讯作者：
Zuo, Jian
影响因子：
2.8
作者：
Alam, SA;Ikeda, K;Takasaka, T
通讯作者：
Takasaka, T
影响因子：
13.3
作者：
Liu W;Xu L;Wang X;Zhang D;Sun G;Wang M;Wang M;Han Y;Chai R;Wang H
通讯作者：
Wang H
影响因子：
3.1
作者：
Liu Y;Wei M;Mao X;Chen T;Lin P;Wang W
通讯作者：
Wang W
影响因子：
2.8
作者：
Haake, Scott M.;Dinh, Christine T.;Van De Water, Thomas R.
通讯作者：
Van De Water, Thomas R.