Actin Cytoskeleton Remodelling in Apoptosis-induced Proliferation and Tissue Growth Control

细胞凋亡诱导的增殖和组织生长控制中的肌动蛋白细胞骨架重塑

• 批准号: BB/S015701/1
• 负责人: Yun Fan
• 金额: $ 55.21万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS015701%2F1
• 关键词: Actin; Cytoskeleton; Remodelling; Apoptosis; induced

In multicellular organisms including humans, damaged or stressed cells are removed by apoptosis, a programmed cell death pathway, to prevent their detrimental effects on the hosts. Studies in the past decade have revealed that dying cells, before they are removed, can signal their neighbouring surviving cells to induce extra cell divisions and production of new cells which compensates for the loss of dead cells. This process, critical for balancing cell numbers and maintenance of tissue homeostasis, is termed as Apoptosis-induced Proliferation (AiP). Uncontrolled AiP contributes to the development of diseases including cancer. It is therefore important to understand how AiP is controlled at the cellular and molecular level. By using Drosophila as a genetic model organism, we observed an increase of actin filaments, fundamental components of the cellular scaffolding structure - cytoskeleton, in cells emitting AiP signals. Interestingly, such an increase of actin filaments, i.e. actin remodelling, is required for production of reactive oxygen species (ROS) and activation of c-Jun N-terminal kinase (JNK) signalling, two key processes known to trigger AiP. The proposed work is to determine how actin remodelling is regulated in apoptotic dying cells and how it controls ROS production and JNK activation leading to AiP. We will also examine roles of actin remodelling in the development of malignant tumour. Dissecting the molecular control of actin remodelling and its cellular functions in both AiP and tumourigenesis will significantly impact our understanding of physiological tissue recovery and pathological tumour development.

在包括人类在内的多细胞生物体中，受损或应激的细胞通过细胞凋亡（一种程序性细胞死亡途径）去除，以防止它们对宿主的有害影响。过去十年的研究表明，死亡细胞在被移除之前，可以向其邻近的存活细胞发出信号，以诱导额外的细胞分裂和产生新细胞，从而弥补死亡细胞的损失。这个过程对于平衡细胞数量和维持组织稳态至关重要，被称为凋亡诱导的增殖（AiP）。不受控制的AiP有助于包括癌症在内的疾病的发展。因此，重要的是要了解AiP是如何在细胞和分子水平上控制的。通过使用果蝇作为遗传模式生物，我们观察到在发出AiP信号的细胞中，肌动蛋白丝（细胞骨架结构的基本组成部分）的增加。有趣的是，这种肌动蛋白丝的增加，即肌动蛋白重塑，是产生活性氧（ROS）和激活c-Jun N-末端激酶（JNK）信号传导所必需的，这是已知触发AiP的两个关键过程。拟议的工作是确定肌动蛋白重塑是如何调节凋亡垂死细胞，以及它如何控制ROS的产生和JNK激活导致AiP。我们也将研究肌动蛋白重塑在恶性肿瘤发展中的作用。剖析肌动蛋白重塑的分子控制及其在AiP和肿瘤发生中的细胞功能将显著影响我们对生理组织恢复和病理肿瘤发展的理解。

项目成果

The Duality of Caspases in Cancer, as Told through the Fly.

• DOI: 10.3390/ijms22168927
• 发表时间: 2021-08-19
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Hounsell C;Fan Y
• 通讯作者: Fan Y

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

Non-lethal roles of the initiator caspase Dronc in Drosophila

• DOI: 10.3389/fceld.2023.1184041
• 发表时间: 2023-04
• 期刊: PLoS ONE
• 影响因子: 3.7
• 作者: Daniel Domínguez;Yun Fan