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首页> 外文学位 >S-nitrosylated glyceraldehyde-3-phosphate dehydrogenase initiates apoptotic cell death by nuclear translocation following Siah1 binding.
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S-nitrosylated glyceraldehyde-3-phosphate dehydrogenase initiates apoptotic cell death by nuclear translocation following Siah1 binding.

机译：S-亚硝酰甘油醛-3-磷酸脱氢酶通过Siah1结合后的核易位引发凋亡细胞死亡。

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摘要

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classical glycolytic protein known for its pivotal role in energy production. Recent evidence demonstrates that mammalian GAPDH displays a number of diverse activities unrelated to its glycolytic function, including its possible role in apoptosis. Our laboratory has found that GAPDH translocates to the nucleus following a wide range of apoptotic stimuli1. Antisense oligonucleotides targeted to GAPDH decrease nuclear GAPDH and prevent cell death. This thesis attempts to study a mechanism underlying this nuclear translocation and cytotoxicity. GAPDH, which lacks a nuclear localization signal (NLS), bind to the NLS-containing protein Siahl (an E3-ubiquitin-ligase), which mediates GAPDH's nuclear translocation. Nitric oxide (NO) generation following apoptotic stimulation elicits S-nitrosylation of GAPDH, which augments its binding to Siahl. GAPDH stabilizes Siahl facilitating its degradation of nuclear proteins. Activation of macrophages by endotoxin and of neurons by glutamate elicits GAPDH-Siahl binding, nuclear translocation and apoptosis, which are prevented by NO deletion. The NO-S-nitrosylation-GAPDH-Siahl cascade may represent a major molecular mechanism of cytotoxicity.
机译：3-磷酸​​甘油醛脱氢酶（GAPDH）是一种经典的糖酵解蛋白，以其在能量产生中的关键作用而闻名。最近的证据表明，哺乳动物GAPDH表现出许多与其糖酵解功能无关的多种活动，包括其在细胞凋亡中的可能作用。我们的实验室发现，GAPDH在多种凋亡刺激下易位至细胞核。靶向GAPDH的反义寡核苷酸可减少核GAPDH并防止细胞死亡。本文试图研究这种核易位和细胞毒性的机制。缺少核定位信号（NLS）的GAPDH与包含NLS的蛋白质Siahl（E3-泛素连接酶）结合，后者介导GAPDH的核易位。凋亡刺激后产生的一氧化氮（NO）引起GAPDH的S-亚硝基化，从而增强了其与Siahl的结合。 GAPDH稳定了Siahl，促进了其核蛋白的降解。内毒素激活巨噬细胞，谷氨酸激活神经元引发GAPDH-Siahl结合，核易位和细胞凋亡，这可以通过NO缺失来阻止。 NO-S-亚硝基化-GAPDH-Siahl级联反应可能代表了细胞毒性的主要分子机制。

著录项

  • 作者

    Hara, Makoto.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Biology Neuroscience.; Biology Cell.; Biology Molecular.; Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 78 p.
  • 总页数 78
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;细胞生物学;分子遗传学;病理学;
  • 关键词

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