Cullinan Sara B, Diehl J Alan
Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, Department of Cancer Biology, University of Pennsylvania Cancer Center, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
J Biol Chem. 2004 May 7;279(19):20108-17. doi: 10.1074/jbc.M314219200. Epub 2004 Feb 20.
The accumulation of unfolded proteins elicits a cellular response that triggers both pro-survival and pro-apoptotic signaling events. PERK-dependent activation of NF-E2-related factor-2 (Nrf2) is critical for survival signaling during this response; however, the mechanism whereby Nrf2 confers a protective advantage to stressed cells remains to be defined. We now demonstrate that Nrf2 activation contributes to the maintenance of glutathione levels, which in turn functions as a buffer for the accumulation of reactive oxygen species during the unfolded protein response. The deleterious effects of Nrf2 or PERK deficiencies could be attenuated by the restoration of cellular glutathione levels or Nrf2 activity. In addition, the inhibition of reactive oxygen species production attenuated apoptotic induction following endoplasmic reticulum stress. Our data suggest that perturbations in cellular redox status sensitize cells to the harmful effects of endoplasmic reticulum stress, but that other factors are essential for apoptotic commitment.
未折叠蛋白的积累引发细胞反应，触发促生存和促凋亡信号事件。蛋白激酶R样内质网激酶（PERK）依赖的核因子E2相关因子2（Nrf2）激活对于此反应中的生存信号至关重要；然而，Nrf2赋予应激细胞保护优势的机制仍有待确定。我们现在证明，Nrf2激活有助于维持谷胱甘肽水平，而谷胱甘肽水平反过来又作为未折叠蛋白反应期间活性氧积累的缓冲剂。Nrf2或PERK缺陷的有害影响可通过恢复细胞谷胱甘肽水平或Nrf2活性来减轻。此外，活性氧产生的抑制减弱了内质网应激后的凋亡诱导。我们的数据表明，细胞氧化还原状态的扰动使细胞对内质网应激的有害影响敏感，但其他因素对于凋亡的发生至关重要。
