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解析核糖体负载的异构体 mRNA 谱定义了肾癌中 HIF 和 mTOR 失调的相互作用。

Isoform-resolved mRNA profiling of ribosome load defines interplay of HIF and mTOR dysregulation in kidney cancer.

机构信息

The Francis Crick Institute, London, UK.

Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

出版信息

Nat Struct Mol Biol. 2022 Sep;29(9):871-880. doi: 10.1038/s41594-022-00819-2. Epub 2022 Sep 12.

DOI:10.1038/s41594-022-00819-2
PMID:36097292
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9507966/
Abstract

Hypoxia inducible factor (HIF) and mammalian target of rapamycin (mTOR) pathways orchestrate responses to oxygen and nutrient availability. These pathways are frequently dysregulated in cancer, but their interplay is poorly understood, in part because of difficulties in simultaneous measurement of global and mRNA-specific translation. Here, we describe a workflow for measurement of ribosome load of mRNAs resolved by their transcription start sites (TSSs). Its application to kidney cancer cells reveals extensive translational reprogramming by mTOR, strongly affecting many metabolic enzymes and pathways. By contrast, global effects of HIF on translation are limited, and we do not observe reported translational activation by HIF2A. In contrast, HIF-dependent alterations in TSS usage are associated with robust changes in translational efficiency in a subset of genes. Analyses of the interplay of HIF and mTOR reveal that specific classes of HIF1A and HIF2A transcriptional target gene manifest different sensitivity to mTOR, in a manner that supports combined use of HIF2A and mTOR inhibitors in treatment of kidney cancer.

摘要

缺氧诱导因子 (HIF) 和哺乳动物雷帕霉素靶蛋白 (mTOR) 通路协调对氧气和营养可用性的反应。这些通路在癌症中经常失调，但它们的相互作用知之甚少，部分原因是难以同时测量全局和 mRNA 特异性翻译。在这里，我们描述了一种用于测量通过转录起始位点 (TSS) 解析的 mRNA 核糖体负载的工作流程。将其应用于肾癌细胞，揭示了 mTOR 对翻译的广泛重编程，强烈影响许多代谢酶和途径。相比之下，HIF 对翻译的全局影响是有限的，我们没有观察到 HIF2A 报道的翻译激活。相比之下，HIF 依赖性 TSS 使用的改变与一组基因中翻译效率的显著变化相关。对 HIF 和 mTOR 相互作用的分析表明，HIF1A 和 HIF2A 转录靶基因的特定类别对 mTOR 的敏感性不同，这支持在治疗肾癌时联合使用 HIF2A 和 mTOR 抑制剂。

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2
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Nat Med. 2020 Oct;26(10):1519-1530. doi: 10.1038/s41591-020-1093-z. Epub 2020 Oct 5.
3
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bioRxiv. 2024 Dec 10:2024.10.10.617658. doi: 10.1101/2024.10.10.617658.
4
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Nat Commun. 2024 Aug 26;15(1):7061. doi: 10.1038/s41467-024-51258-0.
5
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Sci Adv. 2024 Jul 12;10(28):eadl5606. doi: 10.1126/sciadv.adl5606. Epub 2024 Jul 10.
6
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7
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8
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