Determining cellular processes underlying apoptosis-induced cell proliferation through kinase analysis

通过激酶分析确定细胞凋亡诱导的细胞增殖的细胞过程

• 批准号: BB/M010880/1
• 负责人: Yun Fan
• 金额: $ 55.5万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM010880%2F1
• 关键词: Determining; cellular; processes; underlying; apoptosis

A balance between cell death and birth is critical for health of multi-cellular organisms including humans. Disruption of such a balance can lead to many diseases including cancer and degenerative disorders. It is therefore important to understand how cell death and birth are coordinated. Recent work by us and others discovered an unexpected communication initiated from dying cells. Signals emitted from dying cells trigger their neighbouring cells to divide and generate new cells which can compensate for the cell loss. This process is termed Apoptosis-induced Proliferation (AiP). However, it remains elusive how AiP is activated and regulated at the molecular level. The proposed research aims to advance our understanding of AiP. For this purpose, we chose the fruit-fly Drosophila which is a powerful model organism to investigate the regulatory gene network that mediates cellular communication in vivo. We have developed unique assays in Drosophila using either tissue overgrowth or tissue regeneration as sensitive readouts of AiP. These readouts allow quick identification and analysis of novel AiP regulators. By employing these assays we have identified 26 new regulatory genes of AiP. The functions of these genes revealed two key cellular processes underlying AiP. One process is remodelling of the cytoskeleton, the cellular scaffolding, while the other is called autophagy which is a process critical for the maintenance of energy balance in a cell. The proposed work is to determine roles of these key cellular processes and other identified new regulators in mediating AiP. The outcome of this research will help us understand how dying cells talk to their neighbours to induce cell replacement. As AiP is relevant to both regeneration (tissue repair) and tumour growth (cancer) in mammals including humans, the proposed work can provide potential drug targets for regenerative medicine and cancer therapy.

细胞死亡和出生之间的平衡对于包括人类在内的多细胞生物体的健康至关重要。这种平衡的破坏可能导致许多疾病，包括癌症和退行性疾病。因此，重要的是要了解细胞死亡和出生是如何协调的。我们和其他人最近的工作发现了一种由垂死细胞发起的意想不到的通信。从垂死细胞发出的信号触发它们的邻近细胞分裂并产生新的细胞，这些细胞可以补偿细胞损失。这个过程被称为凋亡诱导的增殖（AiP）。然而，AiP如何在分子水平上被激活和调节仍然是难以捉摸的。这项研究旨在促进我们对AiP的理解。为此，我们选择了果蝇这是一个强大的模式生物，以研究调控基因网络，介导的细胞通讯在体内。我们已经开发了独特的检测方法，在果蝇中使用组织过度生长或组织再生作为AiP的敏感读数。这些读数允许快速识别和分析新型AiP调节器。通过这些实验，我们已经确定了26个新的AiP调控基因。这些基因的功能揭示了AiP背后的两个关键细胞过程。一个过程是细胞骨架的重塑，细胞支架，而另一个被称为自噬，这是维持细胞能量平衡的关键过程。拟议的工作是确定这些关键的细胞过程和其他确定的新的监管机构在介导AiP的作用。这项研究的结果将帮助我们了解垂死细胞如何与它们的邻居交谈以诱导细胞替换。由于AiP与包括人类在内的哺乳动物的再生（组织修复）和肿瘤生长（癌症）有关，因此拟议的工作可以为再生医学和癌症治疗提供潜在的药物靶点。

项目成果

Plasma Membrane Localization of Apoptotic Caspases for Non-apoptotic Functions.

• DOI: 10.1016/j.devcel.2018.04.020
• 发表时间: 2018-05-21
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Amcheslavsky A;Wang S;Fogarty CE;Lindblad JL;Fan Y;Bergmann A
• 通讯作者: Bergmann A

Actin remodeling mediates ROS production and JNK activation to drive apoptosis-induced proliferation.

• DOI: 10.1371/journal.pgen.1010533
• 发表时间: 2022-12
• 期刊: PLoS genetics
• 影响因子: 4.5

Autophagy-independent function of Atg1 for apoptosis-induced compensatory proliferation.

• DOI: 10.1186/s12915-016-0293-y
• 发表时间: 2016-08-19
• 期刊: BMC biology
• 影响因子: 5.4
• 作者: Li M;Lindblad JL;Perez E;Bergmann A;Fan Y
• 通讯作者: Fan Y

The Drosophila TNF Eiger activates caspase-dependent necrosis when apoptosis is blocked

• DOI: 10.1101/304964
• 发表时间: 2018-04
• 期刊: bioRxiv
• 作者: Mingli Li;Yun Fan

Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages.

• DOI: 10.1016/j.cub.2015.12.064
• 发表时间: 2016-03-07
• 期刊: Current biology : CB
• 作者: Fogarty CE;Diwanji N;Lindblad JL;Tare M;Amcheslavsky A;Makhijani K;Brückner K;Fan Y;Bergmann A
• 通讯作者: Bergmann A