Institute of Biochemistry, Charité - University Medicine Berlin Berlin, Germany.
Front Mol Neurosci. 2011 Jul 28;4:12. doi: 10.3389/fnmol.2011.00012. eCollection 2011.
Embryo development relies on the complex interplay of the basic cellular processes including proliferation, differentiation, and apoptotic cell death. Precise regulation of these events is the basis for the establishment of embryonic structures and the organ development. Beginning with fertilization of the oocyte until delivery the developing embryo encounters changing environmental conditions such as varying levels of oxygen, which can give rise to reactive oxygen species (ROS). These challenges are met by the embryo with metabolic adaptations and by an array of anti-oxidative mechanisms. ROS can be deleterious by modifying biological molecules including lipids, proteins, and nucleic acids and may induce abnormal development or even embryonic lethality. On the other hand ROS are vital players of various signaling cascades that affect the balance between cell growth, differentiation, and death. An imbalance or dysregulation of these biological processes may generate cells with abnormal growth and is therefore potentially teratogenic and tumorigenic. Thus, a precise balance between processes generating ROS and those decomposing ROS is critical for normal embryo development. One tier of the cellular protective system against ROS constitutes the family of selenium-dependent glutathione peroxidases (GPx). These enzymes reduce hydroperoxides to the corresponding alcohols at the expense of reduced glutathione. Of special interest within this protein family is the moonlighting enzyme glutathione peroxidase 4 (Gpx4). This enzyme is a scavenger of lipophilic hydroperoxides on one hand, but on the other hand can be transformed into an enzymatically inactive cellular structural component. GPx4 deficiency - in contrast to all other GPx family members - leads to abnormal embryo development and finally produces a lethal phenotype in mice. This review is aimed at summarizing the current knowledge on GPx isoforms during embryo development and tumor development with an emphasis on GPx4.
胚胎发育依赖于包括增殖、分化和细胞凋亡等基本细胞过程的复杂相互作用。这些事件的精确调控是胚胎结构和器官发育建立的基础。从卵母细胞受精到分娩，发育中的胚胎会遇到不断变化的环境条件，如氧浓度的变化，这可能会产生活性氧（ROS）。胚胎通过代谢适应和一系列抗氧化机制来应对这些挑战。ROS 通过修饰生物分子（包括脂质、蛋白质和核酸）而具有危害性，并可能导致异常发育甚至胚胎致死。另一方面，ROS 是各种信号级联反应的重要参与者，这些信号级联反应影响细胞生长、分化和死亡之间的平衡。这些生物过程的不平衡或失调可能会导致异常生长的细胞，因此具有潜在的致畸性和致瘤性。因此，产生 ROS 和分解 ROS 的过程之间的精确平衡对于正常胚胎发育至关重要。细胞保护系统抵御 ROS 的一个层次是硒依赖性谷胱甘肽过氧化物酶（GPx）家族。这些酶以还原型谷胱甘肽为代价将过氧化物还原为相应的醇。在这个蛋白质家族中，特别引人注目的是月光酶谷胱甘肽过氧化物酶 4（Gpx4）。一方面，这种酶是亲脂性过氧化物的清除剂，但另一方面，它可以转化为无酶活性的细胞结构成分。与所有其他 GPx 家族成员不同，Gpx4 缺乏会导致胚胎发育异常，最终导致小鼠产生致命表型。这篇综述旨在总结 GPx 同工酶在胚胎发育和肿瘤发育过程中的最新知识，重点介绍 Gpx4。
