Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.
Biochem Biophys Res Commun. 2013 Aug 30;438(3):500-6. doi: 10.1016/j.bbrc.2013.07.107. Epub 2013 Aug 2.
Pro-apoptotic signaling instigated by endoplasmic reticulum (ER) stress is tightly governed by the BH3-only proteins like Noxa and Bim, which help trigger apoptosis, in part by inactivating mitochondria protecting proteins like Mcl-1. Bim/Noxa-based pro-apoptotic signaling has been implicated for various ER stressors but not yet for those causing "ER-focused" production of severe oxidative stress. In the present study we found that photo-oxidative (phox)-ER stress induced by hypericin-based photodynamic therapy is associated with activation of PERK (an ER sessile, stress sensor), robust induction of CHOP (a pro-apoptotic transcription factor) and induction of Bim and Noxa (accompanied by an eventual drop in Mcl-1 levels). Interestingly Noxa, but not Bim, contributed toward phox-ER stress induced apoptosis, regulated by PERK in a CHOP-independent, temporally-defined manner. These observations shed further light on complex signaling pathways elicited byphox-ER stress and vouch for directing more investigation toward the role of PERK in cell death governance.
内质网 (ER) 应激引发的促凋亡信号受到 BH3 仅蛋白的严格控制，如 Noxa 和 Bim，它们有助于触发细胞凋亡，部分是通过使 Mcl-1 等线粒体保护蛋白失活。基于 Bim/Noxa 的促凋亡信号已被牵连到各种 ER 应激源中，但尚未涉及到导致“ER 集中”产生严重氧化应激的应激源。在本研究中，我们发现，基于金丝桃素的光动力疗法引起的光氧化（phox）-ER 应激与 PERK（ER 固定、应激传感器）的激活、CHOP（促凋亡转录因子）的强烈诱导以及 Bim 和 Noxa 的诱导（伴随着 Mcl-1 水平的最终下降）有关。有趣的是，Noxa 而不是 Bim 对 phox-ER 应激诱导的细胞凋亡有贡献，这是由 PERK 以 CHOP 独立、时间限定的方式调节的。这些观察结果进一步阐明了由 phox-ER 应激引发的复杂信号通路，并证明了 PERK 在细胞死亡治理中的作用值得进一步研究。
