『珍藏版』Science综述 | 整合应激反应——从机制到复杂疾病 - 知乎
整合应激反应 （integrated stress response ISR）是蛋白质稳态失调时诱发的信号中心调控网络，主要以控制蛋白质合成速率来实现。 2020年4月24日，美国贝勒医学院的 Mauro Costa-Mattioli 和UCSF大学的 Peter Walter 在 Science 上发表题为 The integrated stress response: From mechanism to disease 综述。 本综述总结了ISR调控机制以及ISR异常时如何导致复杂疾病发生，包括认知障碍、神经退行性疾病、肿瘤和糖尿病等。 最后作者指出开发出调控ISR的有效药 …
Activation of the integrated stress response by inhibitors of
2023年9月8日 · Reconstitution of ISR activation with recombinant proteins demonstrates that PERK and PKR inhibitors directly activate dimeric GCN2, following a Gaussian activation-inhibition curve, with...
Activation of Gcn2 by small molecules designed to be inhibitors
The integrated stress response (ISR) is an important mechanism by which cells confer protection against environmental stresses. Central to the ISR is a collection of related protein kinases that monitor stress conditions, such as Gcn2 (EIF2AK4) …
General control nonderepressible 2 (GCN2) as a therapeutic target …
The function of General Control Nonderepressible 2 (GCN2), an evolutionary-conserved component of the integrated stress response (ISR), has been well-documented across organisms from yeast to mammals. Recently GCN2 has also gained attention for its ...
An ISR-independent role of GCN2 prevents excessive ribosome …
GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omics approach, we uncover an ISR-independent role of GCN2.
GCN2 kinase activation by ATP-competitive kinase inhibitors
2021年12月23日 · A genome-wide CRISPR screen revealed that loss of general control nonderepressible 2 (GCN2) kinase increases cellular resistance to the pan-ErbB inhibitor neratinib with neratinib directly...
Towards a model of GCN2 activation - PubMed
2019年10月31日 · Upon amino acid deficiency, GCN2 is activated and initiates the ISR by phosphorylating the translation initiation factor eIF2α, stalling protein translation, and activating the transcription factor ATF4, which in turn up-regulates autophagy and biosynthesis pathways.
Cell子刊：激活GCN2，可代谢重编程T细胞，增强其抗肿瘤免疫
在这项最新研究中，研究团队发现，使用GCN2激动剂halofuginone（halo）在体外激活效应性CD8+ T细胞的氨基酸饥饿反应，可以增强其氧化代谢和效应器功能。
Multiple mechanisms activate GCN2 eIF2 kinase in response to …
2024年2月28日 · The eIF2 kinase GCN2 is a first responder in the ISR that is activated by amino acid depletion and other stresses not directly related to nutrients. Two mechanisms are suggested to trigger an ordered process of GCN2 activation during stress: GCN2 monitoring stress via accumulating uncharged tRNAs or by stalled and colliding ribosomes.
Multiple Roles of the Stress Sensor GCN2 in Immune Cells
GCN2 can sense stalled ribosomes and activate the eIF-2α/ATF4 downstream signaling pathway to promote ISR, which protects neurons against ribosome stalling-mediated cell death [95].
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