Downregulation of YAP Activity Restricts P53 Hyperactivation to Promote Cell Survival in Confinement.
Downregulation of YAP Activity Restricts P53 Hyperactivation to Promote Cell Survival in Confinement.
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DOI：
10.1002/advs.202302228
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发表时间：
2023-08
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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通过限制三维（3D）地形的细胞迁移可导致核膜完整性丧失，DNA损伤和基因组不稳定。尽管有这些有害的现象，细胞暂时暴露于禁闭通常不会死亡。对于长期监禁的细胞是否也是如此，目前尚不清楚。为了研究这一点，利用光模式和微流体技术制造了一种高通量装置，该装置绕过了以前细胞限制模型的限制，并能够在具有生理相关长度尺度的微通道中长时间培养单细胞。本研究结果表明，持续暴露于密闭环境中可引发频繁的核膜破裂事件，从而促进P53激活和细胞凋亡。迁移细胞最终通过下调YAP活性来适应禁闭并逃避细胞死亡。限制诱导的YAP1/2向细胞质易位导致YAP活性降低，从而抑制核膜破裂的发生率，并消除P53介导的细胞死亡。总的来说，这项工作建立了先进的、高通量的仿生模型，以便更好地理解健康和疾病中的细胞行为，并强调了地形线索和机械转导途径在细胞生命和死亡调节中的关键作用。本研究采用新型微流体装置来演示迁移细胞如何响应和适应长期禁闭。持续暴露于使细胞核变形的受限微环境中会降低细胞活力。然而，YAP易位到细胞质有助于细胞适应封闭，减少核膜破裂事件的频率，防止P53介导的细胞死亡。
Cell migration through confining three dimensional (3D) topographies can lead to loss of nuclear envelope integrity, DNA damage, and genomic instability. Despite these detrimental phenomena, cells transiently exposed to confinement do not usually die. Whether this is also true for cells subjected to long‐term confinement remains unclear at present. To investigate this, photopatterning and microfluidics are employed to fabricate a high‐throughput device that circumvents limitations of previous cell confinement models and enables prolonged culture of single cells in microchannels with physiologically relevant length scales. The results of this study show that continuous exposure to tight confinement can trigger frequent nuclear envelope rupture events, which in turn promote P53 activation and cell apoptosis. Migrating cells eventually adapt to confinement and evade cell death by downregulating YAP activity. Reduced YAP activity, which is the consequence of confinement‐induced YAP1/2 translocation to the cytoplasm, suppresses the incidence of nuclear envelope rupture and abolishes P53‐mediated cell death. Cumulatively, this work establishes advanced, high‐throughput biomimetic models for better understanding cell behavior in health and disease, and underscores the critical role of topographical cues and mechanotransduction pathways in the regulation of cell life and death. This study employs novel microfluidic devices to demonstrate how migrating cells respond and adapt to long‐term confinement. Constant exposure to confined microenvironments that deform the nucleus can reduce cell viability. However, YAP translocation to the cytoplasm helps cells adapt to confinement by reducing the frequency of nuclear envelope rupture events and preventing P53‐mediated cell death.
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影响因子：
7.8
作者：
Mistriotis, Panagiotis;Wisniewski, Emily O.;Konstantopoulos, Konstantinos
通讯作者：
Konstantopoulos, Konstantinos
影响因子：
13.6
作者：
Lee HP;Alisafaei F;Adebawale K;Chang J;Shenoy VB;Chaudhuri O
通讯作者：
Chaudhuri O
DOI：
10.1161/atvbaha.121.317365
发表时间：
2022-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Daoud F;Arévalo Martinez M;Holmberg J;Alajbegovic A;Ali N;Rippe C;Swärd K;Albinsson S
通讯作者：
Albinsson S
影响因子：
3.9
作者：
Ahearne, M;Yang, Y;Liu, KK
通讯作者：
Liu, KK
影响因子：
21.3
作者：
Furlow PW;Zhang S;Soong TD;Halberg N;Goodarzi H;Mangrum C;Wu YG;Elemento O;Tavazoie SF
通讯作者：
Tavazoie SF