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首页> 外文学位 >The role ofp53 in death receptor-mediated apoptosis of testicular germ cells in response to mono-(2-ethylhexyl) phthalate treatment.
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The role ofp53 in death receptor-mediated apoptosis of testicular germ cells in response to mono-(2-ethylhexyl) phthalate treatment.

机译：p53在邻苯二甲酸单-（2-乙基己基）酯处理中在死亡受体介导的睾丸生殖细胞凋亡中的作用。

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摘要

Mono-(2-ethylhexyl) phthalate (MEHP) is the toxic metabolite of the common plasticizer di-(2-ethylhexyl) phthalate (DEHP). Exposure to DEHP or MEHP typically leads to testicular atrophy in laboratory animals. The prevalence of DEHP as an environmental contaminant is therefore cause for concern due to its potential to affect human testicular function and fertility. In the testis, MEHP induces the injury of the supportive cells called Sertoli cells, leading to Fas death receptor-dependent apoptotic elimination of germ cells. This dissertation examines the molecular mechanisms that lead to this loss of germ cells resulting from testicular exposure to MEHP. The p53 tumor suppressor protein is proposed as the cellular stress sensor that sensitizes specific germ cells to Fas-dependent cell death in response to the MEHP-induced Sertoli cell injury. This is based upon recent reports that demonstrate p53's ability to initiate the localization of Fas to the plasma membrane of cells in a transcription-independent manner, in addition to its ability to transcribe various pro-apoptotic proteins including Fas.; In experiments involving the exposure of pre-pubertal p53 wild-type and mutant mice (C57 x 129S/v) to a single oral dose of 1g MEHP/kg body weight, we were able to demonstrate that mice lacking the p53 gene were partially protected from the testicular toxicity induced by MEHP. These studies enabled us to establish that a lack of p53 expression affected the activation of the Fas pathway in germ cells after MEHP exposure, partly by affecting Fas membrane localization and also by influencing the cellular retention of an inhibitor of this pathway, the c-FLIP (L) protein. To further clarify these results, we examined the effect of Fas activation in GC-2spd (ts) cells, which are germ cells that demonstrate variable activation of p53 depending on the temperature that they are maintained at. The activation of the p53 protein increased the sensitivity of GC-2 cells to undergo Fas-mediated apoptosis by modulating Fas expression on the germ cell membrane. Additionally, activation of Fas caused an increased tagging of c-FLIP (L) with ubiquitin, indicating its targeting for degradation. Thus the p53 status of GC-2 cells influenced the membrane expression of Fas, subsequently influencing the degradation of the anti-apoptotic protein c-FLIP (L). In summary, the results indicate that p53 promotes Fas activated germ cell apoptosis in response to MEHP-induced Sertoli cell injury, by instigating the degradation of c-FLIP (L) protein via its ubiquitinylation.
机译：邻苯二甲酸单（2-乙基己基）酯（MEHP）是常见的增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）的有毒代谢产物。暴露于DEHP或MEHP通常会导致实验动物睾丸萎缩。由于DEHP可能影响人体睾丸功能和生育能力，因此其作为环境污染物的流行备受关注。在睾丸中，MEHP诱导称为Sertoli细胞的支持细胞的损伤，从而导致Fas死亡受体依赖性的生殖细胞凋亡消除。本文探讨了睾丸暴露于MEHP导致生殖细胞损失的分子机制。有人提出将p53肿瘤抑制蛋白作为细胞应激传感器，使特定生殖细胞对MEHP诱导的支持细胞损伤引起的Fas依赖性细胞死亡敏感。这是基于最近的报道，这些报道证明了p53能够以转录非依赖性的方式启动Fas定位于细胞质膜的能力，以及其转录包括Fas在内的各种促凋亡蛋白的能力。在涉及将青春期前p53野生型和突变小鼠（C57 x 129S / v）暴露于1g MEHP / kg体重的单次口服剂量的实验中，我们能够证明缺乏p53基因的小鼠受到了部分保护从MEHP引起的睾丸毒性这些研究使我们能够确定，p53表达的缺失会影响MEHP暴露后生殖细胞中Fas途径的激活，部分原因是影响Fas膜的定位，也影响该途径的抑制剂c-FLIP的细胞保留（L）蛋白。为了进一步阐明这些结果，我们研究了Fas活化在GC-2spd（ts）细胞中的作用，该细胞是根据其维持温度证明p53可变活化的生殖细胞。 p53蛋白的激活通过调节生殖细胞膜上Fas的表达来增加GC-2细胞经历Fas介导的凋亡的敏感性。此外，Fas的激活导致c-FLIP（L）与泛素的标记增加，表明其靶向降解。因此，GC-2细胞的p53状态影响Fas的膜表达，随后影响抗凋亡蛋白c-FLIP（L）的降解。总之，结果表明，p53通过促进c-FLIP（L）蛋白的泛素化降解来促进MEHP诱导的Sertoli细胞损伤引起Fas活化的生殖细胞凋亡。

著录项

  • 作者

    Chandrasekaran, Yamini.;

  • 作者单位

    The University of Texas at Austin.;

  • 授予单位 The University of Texas at Austin.;
  • 学科 Health Sciences Toxicology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 155 p.
  • 总页数 155
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 毒物学（毒理学）;
  • 关键词

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