Genetic models of apoptosis-induced proliferation decipher activation of JNK and identify a requirement of EGFR signaling for tissue regenerative responses in Drosophila.
Genetic models of apoptosis-induced proliferation decipher activation of JNK and identify a requirement of EGFR signaling for tissue regenerative responses in Drosophila.
复制标题
细胞凋亡引起的JNK的增殖解密激活的遗传模型，并确定了果蝇中EGFR信号传导对组织再生反应的需求。
DOI：
10.1371/journal.pgen.1004131
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发表时间：
2014-01
期刊：
影响因子：
4.5
通讯作者：
Bergmann A
中科院分区：
文献类型：
--
作者：
Fan Y;Wang S;Hernandez J;Yenigun VB;Hertlein G;Fogarty CE;Lindblad JL;Bergmann A
最近在几个模式生物中的研究表明，凋亡细胞能够刺激邻近存活的细胞经历额外的增殖，这种现象被称为凋亡诱导增殖。这一过程严重依赖于凋亡的caspase，如Dronc，果蝇中的Caspase-9同源基因，可能对肿瘤的发生有重要的影响。虽然Dronc可以诱导Jun N末端激酶(JNK)的活性以诱导细胞凋亡，但这种激活的机制细节很大程度上还不清楚。JNK活性是发生在死亡细胞还是存活细胞中也是有争议的。Wnt和BMP家族的信号分子参与了细胞凋亡诱导的增殖，但目前还不清楚它们是否是唯一的信号分子。为了解决这些问题，我们开发了一种有效的方法来筛选和鉴定调控或介导细胞凋亡诱导的增殖的基因。我们已经确定了作用于JNK活性上游的基因子集，包括Rho1。我们还证明，JNK的激活既发生在凋亡细胞中，也发生在邻近存活的细胞中。在基因筛查中，我们发现通过EGFR途径的信号对JNK信号下游的凋亡诱导的增殖起重要作用。这些数据强调了基因筛选的重要性，并有望更好地理解细胞凋亡诱导的增殖机制。近年来的研究表明，凋亡的半胱氨酸天冬氨酸酶不仅能诱导细胞凋亡，而且还具有非凋亡功能。这些功能之一是诱导凋亡增殖，这是最近发现的一种现象，通过这种现象，凋亡的细胞可以诱导存活的邻近细胞的增殖。这一现象可能对干细胞活性、组织再生和肿瘤发生有重要影响。在这里，我们描述了一个凋亡诱导增殖的遗传模型的发展，并利用这个模型进行方便和公正的基因筛选，以确定参与这一过程的基因。我们测试了我们的RNAi转基因株系的突变体，目标是凋亡途径和JNK信号的核心成分，JNK信号是一种已知的凋亡诱导增殖的中介。这些分析证明了该系统用于系统遗传筛选的可行性，并确定了JNK上游的几个新基因，这些基因与细胞凋亡诱导的增殖有关。最后，我们在染色体臂2L的试点筛查中测试了该模型，并确定了果蝇中的EGF配体SPI在诱导细胞凋亡的增殖中起重要作用。我们证实了EGF参与了一个真正的细胞凋亡诱导的再生系统。这些数据强调了基因筛选的重要性，并有望更好地理解细胞凋亡诱导的增殖和再生机制。
Recent work in several model organisms has revealed that apoptotic cells are able to stimulate neighboring surviving cells to undergo additional proliferation, a phenomenon termed apoptosis-induced proliferation. This process depends critically on apoptotic caspases such as Dronc, the Caspase-9 ortholog in Drosophila, and may have important implications for tumorigenesis. While it is known that Dronc can induce the activity of Jun N-terminal kinase (JNK) for apoptosis-induced proliferation, the mechanistic details of this activation are largely unknown. It is also controversial if JNK activity occurs in dying or in surviving cells. Signaling molecules of the Wnt and BMP families have been implicated in apoptosis-induced proliferation, but it is unclear if they are the only ones. To address these questions, we have developed an efficient assay for screening and identification of genes that regulate or mediate apoptosis-induced proliferation. We have identified a subset of genes acting upstream of JNK activity including Rho1. We also demonstrate that JNK activation occurs both in apoptotic cells as well as in neighboring surviving cells. In a genetic screen, we identified signaling by the EGFR pathway as important for apoptosis-induced proliferation acting downstream of JNK signaling. These data underscore the importance of genetic screening and promise an improved understanding of the mechanisms of apoptosis-induced proliferation. Work in recent years has revealed that apoptotic caspases not only induce apoptosis, but also have non-apoptotic functions. One of these functions is apoptosis-induced proliferation, a relatively recently discovered phenomenon by which apoptotic cells induce proliferation of surviving neighboring cells. This phenomenon may have important implications for stem cell activity, tissue regeneration and tumorigenesis. Here, we describe the development of a genetic model of apoptosis-induced proliferation and the use of this model for convenient and unbiased genetic screening to identify genes involved in the process. We tested mutants of our RNAi transgenic lines targeting the core components of the apoptotic pathway and of JNK signaling, a known mediator of apoptosis-induced proliferation. These assays demonstrate the feasibility of the system for systematic genetic screening and identified several new genes upstream of JNK that are involved in apoptosis-induced proliferation. Finally, we tested the model in a pilot screen for chromosome arm 2L and identified spi, the EGF ligand in flies, as important for apoptosis-induced proliferation. We confirmed the involvement of EGF in a genuine apoptosis-induced regeneration system. These data underscore the importance of genetic screening and promise an improved understanding of the mechanisms of apoptosis-induced proliferation and regeneration.
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