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干扰素转录上调癌细胞中 MLKL 的表达。

Interferons Transcriptionally Up-Regulate MLKL Expression in Cancer Cells.

机构信息

Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.

Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.

出版信息

Neoplasia. 2019 Jan;21(1):74-81. doi: 10.1016/j.neo.2018.11.002. Epub 2018 Dec 3.

DOI:10.1016/j.neo.2018.11.002
PMID:30521981
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6310689/
Abstract

Interferons (IFNs) are key players in the tumor immune response and act by inducing the expression of IFN-stimulated genes (ISGs). Here, we identify the mixed-lineage kinase domain-like pseudokinase (MLKL) as an ISG in various cancer cell lines. Both type I and type II IFNs increase the expression of MLKL indicating that MLKL up-regulation is a general feature of IFN signaling. IFNγ up-regulates mRNA as well as protein levels of MLKL demonstrating that IFNγ transcriptionally regulates MLKL. This notion is further supported by Actinomycin D chase experiments showing that IFNγ-stimulated up-regulation of MLKL is prevented in the presence of the transcriptional inhibitor Actinomycin D. Also, knockdown of the transcription factor IFN-regulatory factor 1 (IRF1) and signal transducer and activator of transcription (STAT) 1 as well as knockout of IRF1 significantly attenuate IFNγ-mediated induction of MLKL mRNA levels. Up-regulation of MLKL by IFNγ provides a valuable tool to sensitize cells towards necroptotic cell death and to overcome apoptosis resistance of cancer cells.

摘要

干扰素 (IFNs) 是肿瘤免疫反应的关键参与者，通过诱导干扰素刺激基因 (ISGs) 的表达来发挥作用。在这里，我们鉴定出混合谱系激酶结构域样伪激酶 (MLKL) 是各种癌细胞系中的 ISG。I 型和 II 型 IFNs 均增加 MLKL 的表达，表明 MLKL 的上调是 IFN 信号的普遍特征。IFNγ 上调 MLKL 的 mRNA 以及蛋白水平，表明 IFNγ 转录调控 MLKL。这种观点进一步得到放线菌素 D 追踪实验的支持，该实验表明，在存在转录抑制剂放线菌素 D 的情况下，IFNγ 刺激的 MLKL 上调被阻止。此外，转录因子干扰素调节因子 1 (IRF1) 和信号转导和转录激活因子 1 (STAT1) 的敲低以及 IRF1 的敲除均显著减弱 IFNγ 介导的 MLKL mRNA 水平的诱导。IFNγ 对 MLKL 的上调为使细胞对坏死性细胞死亡敏感并克服癌细胞的凋亡抵抗提供了有价值的工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/c2f1e665c5a2/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/09117c031b44/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/00a723b97235/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/6587ae296572/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/866538564a63/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/278c00ad9461/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/c2f1e665c5a2/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/09117c031b44/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/00a723b97235/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/6587ae296572/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/866538564a63/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/278c00ad9461/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d0a/6310689/c2f1e665c5a2/gr6.jpg

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