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Nature:eIF4F 与致癌蛋白的相互作用

摘要 : 发表于2014年7月27日的《Nature》杂志上的两项研究,两个独立的研究小组揭示“翻译启动因子”eIF4A与致癌蛋白的相互作用。
图示:七个病人中的每个肿瘤样品的eIF4F复合物的形成。

图示:七个病人中的每个肿瘤样品的eIF4F复合物的形成。

一些致癌蛋白的表达是在翻译层面上被调控的。Hans-Guido Wendel 及同事发现,依赖于“翻译启动因子”eIF4A的一个子类的编码致癌蛋白和转录因子的mRNA,在它们5′ 未翻译的区域含有一个能形成G-quadruplex的结构。

这些发现可解释为什么silvestrol (一种来自植物的抗癌药物,以依赖于eIF4A的翻译为目标)一般是无毒的,可以被很好地耐受,除非是在依赖于这些蛋白之活性的癌细胞中。

在本期发表的另一项研究中,Stéphan Vagner及同事发现,eIF4F的抑制会与BRAF抑制因子合作来抑制跟BRAF突变相关的黑素瘤的生长。

原文摘要:

eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies

Lise Boussemart, Hélène Malka-Mahieu, Isabelle Girault, Delphine Allard, Oskar Hemmingsson, Gorana Tomasic, Marina Thomas, Christine Basmadjian, Nigel Ribeiro,Frédéric Thuaud, Christina Mateus, Emilie Routier, Nyam Kamsu-Kom, Sandrine Agoussi,Alexander M. Eggermont, Laurent Désaubry, Caroline Robert & Stéphan Vagner

In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS–RAF–MEK–ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K–AKT–mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m7G) at the 5′ end of messenger RNA, thereby modulating the translation of specific mRNAs. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of anin situ method to detect the eIF4E–eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E–eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.

RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer

Andrew L. Wolfe, Kamini Singh, Yi Zhong, Philipp Drewe, Vinagolu K. Rajasekhar, Viraj R. Sanghvi, Konstantinos J. Mavrakis, Man Jiang, Justine E. Roderick, Joni Van der Meulen,Jonathan H. Schatz, Christina M. Rodrigo, Chunying Zhao, Pieter Rondou, Elisa de Stanchina, Julie Teruya-Feldstein, Michelle A. Kelliher, Frank Speleman, John A. Porco,Jerry Pelletier, Gunnar Rätsch & Hans-Guido Wendel

The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5′ untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5′ UTRs of selec cancer genes harbour a targetable requirement for the eIF4A RNA helicase.

对应Nature杂志: 2014年9月4日Nature杂志精选

来源: Nature 浏览次数:268

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