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首页> 外文学位 >Ras activation contributes to outer hair cell apoptosis in the basal turn of the cochlea after cisplatin and gentamicin exposure.
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Ras activation contributes to outer hair cell apoptosis in the basal turn of the cochlea after cisplatin and gentamicin exposure.

机译：在顺铂和庆大霉素暴露后，Ras激活有助于耳蜗基底转弯中外毛细胞凋亡。

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摘要

Increasing evidence suggests that hair cells undergo apoptosis secondary to cisplatin and aminoglycoside exposure. Although growth factors, oxygen free radical scavengers and iron chelators can protect hair cells from ototoxins, the intracellular signaling events leading to hair cell apoptosis have yet to be fully elucidated. To identify possible intracellular mediators of ototoxicity, we treated basal-turn, neonatal, rat hair cells in vitro with several specific intracellular signaling inhibitors, prior to cisplatin or gentamicin exposure. The cell permeable caspase inhibitor, Z-VAD-FMK (150 muM), provided potent protection of hair cells from cisplatin and gentamicin. Since caspases play a critical role in apoptosis, this result supports the apoptotic nature of hair cell death in cisplatin and gentamicin ototoxicity. Histochemical labeling studies using the TUNEL method and anti-activated caspase 3 antibodies further support the apoptotic nature of this hair cell death. The general G-protein inhibitor, GDP-betaS (1 mM), provided potent protection from gentamicin and cisplatin, suggesting involvement of a G-protein in the intracellular pathway linking cisplatin and gentamicin exposure to hair cell apoptosis. ADP-betaS had minimal effect against gentamicin, thus the protection is specific to a G-binding site, rather than a general reaction to nucleotides. Azido-GTP32 photolabeling studies indicated that an approximately 21 kDa G-protein is activated in the organ of Corti after exposure to cisplatin or gentamicin. MALDI/MS analysis of this band matched its sequence with c-H-p21 Ras with a high degree of certainty. A Raf pulldown assay also indicated that a 21 kDa protein binds to Raf in the organ of Corti after gentamicin exposure. The farnesyl transferase inhibitors FTase-inhibitor-1 (50 muM) and FTI-277 (10 muM) provided strong protection against ototoxicity, suggesting the possibility that activation of N- or K-Ras is functionally involved in OHC apoptosis. In contrast, MEK inhibitors increase hair cell loss, indicating hair cells require MEK/ERK for survival. Downstream pathways through which Ras may contribute to hair cell apoptosis include modulation of BAD and JNK phosphorylation.
机译：越来越多的证据表明，毛细胞在顺铂和氨基糖苷暴露后会发生凋亡。尽管生长因子，氧自由基清除剂和铁螯合剂可以保护毛细胞免受毒素的侵害，但导致毛细胞凋亡的细胞内信号传递事件尚未得到充分阐明。为了确定耳毒性的可能的细胞内介质，我们在顺铂或庆大霉素暴露之前，先用几种特定的细胞内信号抑制剂在体外处理了基础转折的新生大鼠毛细胞。可渗透细胞的半胱天冬酶抑制剂Z-VAD-FMK（150μM）为毛细胞提供了有效的保护，使其免受顺铂和庆大霉素的侵害。由于半胱天冬酶在细胞凋亡中起关键作用，因此该结果支持了顺铂和庆大霉素耳毒性中毛细胞死亡的凋亡性质。使用TUNEL方法和抗活化的caspase 3抗体的组织化学标记研究进一步支持了这种毛细胞死亡的凋亡性质。通用的G蛋白抑制剂GDP-betaS（1 mM）提供了针对庆大霉素和顺铂的有效保护，表明G蛋白参与了连接顺铂和庆大霉素暴露于毛细胞凋亡的细胞内途径。 ADP-betaS对庆大霉素的影响极小，因此保护作用是针对G结合位点的，而不是针对核苷酸的一般反应。 Azido-GTP32光标记研究表明，暴露于顺铂或庆大霉素后，Corti器官中激活了约21 kDa G蛋白。该条带的MALDI / MS分析具有较高的确定性，使其序列与c-H-p21 Ras匹配。 Raf下拉试验还表明，庆大霉素暴露后，21 kDa蛋白与Corti器官中的Raf结合。法呢基转移酶抑制剂FTase-inhibitor-1（50μM）和FTI-277（10μM）提供了针对耳毒性的强大保护作用，表明N-或K-Ras的激活在功能上与OHC细胞凋亡有关。相反，MEK抑制剂会增加毛细胞的流失，表明毛细胞需要MEK / ERK才能存活。 Ras可能有助于毛细胞凋亡的下游途径包括BAD和JNK磷酸化的调节。

著录项

  • 作者

    Battaglia, Alex S.;

  • 作者单位

    University of California, San Diego.;

  • 授予单位 University of California, San Diego.;
  • 学科 Biology Molecular.; Health Sciences Pathology.; Health Sciences Toxicology.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 128 p.
  • 总页数 128
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;病理学;毒物学（毒理学）;
  • 关键词

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