Reversal of apoptosis:an in vivo mechanism for cytoprotection and mutagenesis

细胞凋亡在多细胞生物的发育和稳态中起着重要的作用， 删除不需要的结构，并消除异常，受伤或危险的细胞1。此外，针对 细胞凋亡途径是治疗难治性疾病如癌症的重要策略，而 限制细胞凋亡可有益于治疗缺血性损伤和变性疾病。虽然损失-或 凋亡调节因子的功能获得可以人为地允许细胞存活超过正常检查点， 细胞凋亡通常被认为是一种本质上不可逆的过程2，3。然而，我们最近发现了一个 人类和小鼠细胞中晚期凋亡的自然可逆性4，5.死亡的细胞可以逆转凋亡， 幸存下来，尽管已经通过了以前被认为是不归路的检查站， caspase-3激活和DNA损伤。简单地洗掉凋亡诱导物就足以使细胞凋亡发生。 大多数死亡细胞存活，大多数凋亡标志消失，表明逆转 细胞凋亡是一种内源性细胞机制。值得注意的是，虽然大多数细胞完全恢复， 逆转凋亡的细胞保留遗传改变，并在较高的水平上进行致癌转化。 频率高于对照组。我们认为细胞凋亡的逆转可能是一种生理机制， 可以起到几个有益的作用。原则上，在执行阶段阻止细胞凋亡可以促进 细胞的存活，如神经元和心肌细胞，这是难以取代的。替代地或 此外，这种恢复过程，我们称之为anastasis（希腊语为复活），可以促进 遗传和表型多样性响应于引发细胞凋亡的环境或生理应激。 这个有益过程的一个负面副作用是致癌转化。我们已经开发 并测试了一种生物传感器，以检测黑腹果蝇体内经历了anastasis的细胞。在 具体目的1我们将检验以下假设：吻合功能是挽救难以替换的细胞， 从而限制了短暂损伤后的永久性组织损伤。我们还建议开发一个类似的 用于哺乳动物细胞的生物传感器。在具体目标2中，我们建议启动分子生物学的研究。 控制愈合的机制。拟议的工作有可能导致对 治疗退行性疾病和癌症。

Apoptosis plays essential roles in development and homeostasis in multicellular organisms by sculpting tissues, deleting unwanted structures, and eliminating abnormal, injured or dangerous cells1. In addition, targeting apoptotic pathways is an important strategy for treatment of intractable diseases such as cancer, whereas limiting apoptosis may be beneficial for treating ischemic injury and degenerative disorders. Although loss- or gain-of-function of apoptotic regulators can artificially allow cells to survive beyond normal checkpoints, apoptosis is generally assumed to be an intrinsically irreversible process2,3. However, we recently discovered a natural reversibility of late-stage apoptosis in human and mouse cells4,5. Dying cells can reverse apoptosis and survive, despite having passed through checkpoints previously believed to be the point of no return, including caspase-3 activation and DNA damage. Simply washing away apoptotic inducers is sufficient to allow the majority of dying cells to survive and most hallmarks of apoptosis to vanish, indicating that reversal of apoptosis is an endogenous cellular mechanism. Notably, while most cells recover completely, a small fraction of cells that reverse apoptosis retain genetic alterations and undergo oncogenic transformation at a higher frequency than control cells. We propose that reversal of apoptosis may be a physiological mechanism that can serve several beneficial functions. Arrest of apoptosis at the execution stage could in principle promote survival of cells, such as neurons and heart muscle cells, which are difficult to replace. Alternatively or in addition, this recovery process, which we have named anastasis (Greek for rising to life), could promote genetic and phenotypic diversity in response to environmental or physiological stresses that initiate apoptosis. A negative side effect of this otherwise beneficial process is oncogenic transformation. We have developed and tested a biosensor to detect cells that have undergone anastasis in vivo in Drosophila melanogaster. In specific aim 1 we will test the hypothesis that anastasis functions to salvage cells that are difficult to replace, thus limiting permanent tissue damage following transient insults. We also propose to develop a similar biosensor for use in mammalian cells. In specific aim 2 we propose to initiate studies of the molecular mechanisms controlling anastasis. The proposed work has the potential to lead to a new understanding of and treatments for degenerative diseases and cancer.