Division of Pharmaceutical Sciences, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705-2222, USA; Laboratory of Genetics Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.
Division of Pharmaceutical Sciences, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705-2222, USA; Laboratory of Genetics Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.
Dev Biol. 2014 Feb 1;386(1):34-41. doi: 10.1016/j.ydbio.2013.12.005. Epub 2013 Dec 13.
Precise control over activation of the apoptotic machinery is critical for development, tissue homeostasis and disease. In Drosophila, the decision to trigger apoptosis--whether in response to developmental cues or to DNA damage--converges on transcription of inhibitor of apoptosis protein (IAP) antagonists reaper, hid and grim. Here we describe a parallel process that regulates the sensitivity to, rather than the execution of, apoptosis. This process establishes developmental windows that are permissive or restrictive for triggering apoptosis, where the status of cells determines their capacity to die. We characterize one switch in the sensitivity to apoptotic triggers, from restrictive to permissive, that occurs during third-instar larval (L3) development. Early L3 animals are highly resistant to induction of apoptosis by expression of IAP-antagonists, DNA-damaging agents and even knockdown of the IAP diap1. This resistance to apoptosis, however, is lost in wandering L3 animals after acquiring a heightened sensitivity to apoptotic triggers. This switch in sensitivity to death activators is mediated by a change in mechanisms available for activating endogenous caspases, from an apoptosome-independent to an apoptosome-dependent pathway. This switch in apoptotic pathways is regulated in a cell-autonomous manner by the steroid hormone ecdysone, through changes in expression of critical pro-, but not anti-, apoptotic genes. This steroid-controlled switch defines a novel, physiologically-regulated, mechanism for controlling sensitivity to apoptosis and provides new insights into the control of apoptosis during development.
精确控制凋亡机制的激活对于发育、组织稳态和疾病至关重要。在果蝇中，触发凋亡的决定——无论是对发育信号的反应还是对 DNA 损伤的反应——都集中在凋亡抑制蛋白 (IAP) 拮抗剂 reaper、hid 和 grim 的转录上。在这里，我们描述了一个调节凋亡敏感性而不是执行的平行过程。这个过程建立了允许或限制触发凋亡的发育窗口，其中细胞的状态决定了它们死亡的能力。我们描述了一个从限制到允许的凋亡敏感性开关，这个开关发生在第三龄幼虫（L3）发育过程中。早期的 L3 动物对 IAP 拮抗剂、DNA 损伤剂甚至 IAP diap1 的表达诱导凋亡具有高度抗性。然而，在获得对凋亡触发物更高的敏感性后，游走的 L3 动物对凋亡的这种抗性就会丧失。这种对死亡激活剂敏感性的转变是由激活内源性半胱氨酸蛋白酶的机制发生变化介导的，从凋亡体非依赖性途径转变为凋亡体依赖性途径。这种凋亡途径的转变是由类固醇激素蜕皮激素以细胞自主的方式调节的，通过关键促凋亡基因而非抗凋亡基因的表达变化来实现。这种由类固醇控制的开关定义了一种新的、生理调节的控制凋亡敏感性的机制，并为发育过程中凋亡的控制提供了新的见解。
