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JNK 依赖性细胞周期停滞在 G2 期促进组织应激中的存活和衰老样表型。

JNK-dependent cell cycle stalling in G2 promotes survival and senescence-like phenotypes in tissue stress.

机构信息

Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany.

Faculty of Biology, Ludwig-Maximilians-University Munich, Munich, Germany.

出版信息

Elife. 2019 Feb 8;8:e41036. doi: 10.7554/eLife.41036.

DOI:10.7554/eLife.41036
PMID:30735120
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6389326/
Abstract

The restoration of homeostasis after tissue damage relies on proper spatial-temporal control of damage-induced apoptosis and compensatory proliferation. In imaginal discs these processes are coordinated by the stress response pathway JNK. We demonstrate that JNK signaling induces a dose-dependent extension of G2 in tissue damage and tumors, resulting in either transient stalling or a prolonged but reversible cell cycle arrest. G2-stalling is mediated by downregulation of the G2/M-specific phosphatase String(Stg)/Cdc25. Ectopic expression of is sufficient to suppress G2-stalling and reveals roles for stalling in survival, proliferation and paracrine signaling. G2-stalling protects cells from JNK-induced apoptosis, but under chronic conditions, reduces proliferative potential of JNK-signaling cells while promoting non-autonomous proliferation. Thus, transient cell cycle stalling in G2 has key roles in wound healing but becomes detrimental upon chronic JNK overstimulation, with important implications for chronic wound healing pathologies or tumorigenic transformation.

摘要

组织损伤后，内稳态的恢复依赖于损伤诱导的细胞凋亡和代偿性增殖的适当时空控制。在 imaginal discs 中，这些过程由应激反应途径 JNK 协调。我们证明 JNK 信号诱导损伤和肿瘤中 G2 的剂量依赖性延长，导致短暂的停滞或延长但可逆转的细胞周期停滞。G2 停滞是通过下调 G2/M 特异性磷酸酶 String(Stg)/Cdc25 介导的。异位表达足以抑制 G2 停滞，并揭示停滞在存活、增殖和旁分泌信号中的作用。G2 停滞可保护细胞免受 JNK 诱导的凋亡，但在慢性条件下，会降低 JNK 信号细胞的增殖潜力，同时促进非自主性增殖。因此，G2 中的短暂细胞周期停滞在伤口愈合中具有关键作用，但在慢性 JNK 过度刺激时会产生不利影响，这对慢性伤口愈合病理或肿瘤发生转化具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/a37593ae7d41/elife-41036-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/42f99b62671b/elife-41036-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/1a3e5556bd5b/elife-41036-fig1-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/06d81eb9e826/elife-41036-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/ee5a527b48ce/elife-41036-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/e4cb148baed3/elife-41036-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/d89bd8e8ba17/elife-41036-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/849450a47f5d/elife-41036-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/5d60209bfec0/elife-41036-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/dc648abfef42/elife-41036-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/40cb3a8e65d8/elife-41036-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/305692ca5657/elife-41036-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/a37593ae7d41/elife-41036-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/42f99b62671b/elife-41036-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/1a3e5556bd5b/elife-41036-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/ed19fbac3cf2/elife-41036-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/750a10f21605/elife-41036-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/06d81eb9e826/elife-41036-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/ee5a527b48ce/elife-41036-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/e4cb148baed3/elife-41036-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/d89bd8e8ba17/elife-41036-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/849450a47f5d/elife-41036-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/5d60209bfec0/elife-41036-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/dc648abfef42/elife-41036-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/40cb3a8e65d8/elife-41036-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/305692ca5657/elife-41036-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b28/6389326/a37593ae7d41/elife-41036-fig7.jpg

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