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

The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A/DDX2 RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of Silvestrol and related compounds. For example, eIF4A promo...

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Autores principales: Wolfe, Andrew L., Singh, Kamini, Zhong, Yi, Drewe, Philipp, Rajasekhar, Vinagolu K., Sanghvi, Viraj R., Mavrakis, Konstantinos J., Jiang, Man, Roderick, Justine E., Van der Meulen, Joni, Schatz, Jonathan H., Rodrigo, Christina M., Zhao, Chunying, Rondou, Pieter, de Stanchina, Elisa, Teruya-Feldstein, Julie, Kelliher, Michelle A., Speleman, Frank, Porco, John A., Pelletier, Jerry, Rätsch, Gunnar, Wendel, Hans-Guido
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492470/
https://www.ncbi.nlm.nih.gov/pubmed/25079319
http://dx.doi.org/10.1038/nature13485
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author Wolfe, Andrew L.
Singh, Kamini
Zhong, Yi
Drewe, Philipp
Rajasekhar, Vinagolu K.
Sanghvi, Viraj R.
Mavrakis, Konstantinos J.
Jiang, Man
Roderick, Justine E.
Van der Meulen, Joni
Schatz, Jonathan H.
Rodrigo, Christina M.
Zhao, Chunying
Rondou, Pieter
de Stanchina, Elisa
Teruya-Feldstein, Julie
Kelliher, Michelle A.
Speleman, Frank
Porco, John A.
Pelletier, Jerry
Rätsch, Gunnar
Wendel, Hans-Guido
author_facet Wolfe, Andrew L.
Singh, Kamini
Zhong, Yi
Drewe, Philipp
Rajasekhar, Vinagolu K.
Sanghvi, Viraj R.
Mavrakis, Konstantinos J.
Jiang, Man
Roderick, Justine E.
Van der Meulen, Joni
Schatz, Jonathan H.
Rodrigo, Christina M.
Zhao, Chunying
Rondou, Pieter
de Stanchina, Elisa
Teruya-Feldstein, Julie
Kelliher, Michelle A.
Speleman, Frank
Porco, John A.
Pelletier, Jerry
Rätsch, Gunnar
Wendel, Hans-Guido
author_sort Wolfe, Andrew L.
collection PubMed
description The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A/DDX2 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-ALL development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with Silvestrol has powerful therapeutic effects in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5′UTR sequences such as the 12-mer 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, super-enhancer associated transcription factors, and epigenetic regulators. Hence, the 5′UTRs of selected cancer genes harbour a targetable requirement for the eIF4A RNA helicase.
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spelling pubmed-44924702015-07-06 RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer Wolfe, Andrew L. Singh, Kamini Zhong, Yi Drewe, Philipp Rajasekhar, Vinagolu K. Sanghvi, Viraj R. Mavrakis, Konstantinos J. Jiang, Man Roderick, Justine E. Van der Meulen, Joni Schatz, Jonathan H. Rodrigo, Christina M. Zhao, Chunying Rondou, Pieter de Stanchina, Elisa Teruya-Feldstein, Julie Kelliher, Michelle A. Speleman, Frank Porco, John A. Pelletier, Jerry Rätsch, Gunnar Wendel, Hans-Guido Nature Article The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A/DDX2 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-ALL development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with Silvestrol has powerful therapeutic effects in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5′UTR sequences such as the 12-mer 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, super-enhancer associated transcription factors, and epigenetic regulators. Hence, the 5′UTRs of selected cancer genes harbour a targetable requirement for the eIF4A RNA helicase. 2014-07-27 2014-09-04 /pmc/articles/PMC4492470/ /pubmed/25079319 http://dx.doi.org/10.1038/nature13485 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wolfe, Andrew L.
Singh, Kamini
Zhong, Yi
Drewe, Philipp
Rajasekhar, Vinagolu K.
Sanghvi, Viraj R.
Mavrakis, Konstantinos J.
Jiang, Man
Roderick, Justine E.
Van der Meulen, Joni
Schatz, Jonathan H.
Rodrigo, Christina M.
Zhao, Chunying
Rondou, Pieter
de Stanchina, Elisa
Teruya-Feldstein, Julie
Kelliher, Michelle A.
Speleman, Frank
Porco, John A.
Pelletier, Jerry
Rätsch, Gunnar
Wendel, Hans-Guido
RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
title RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
title_full RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
title_fullStr RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
title_full_unstemmed RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
title_short RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
title_sort rna g-quadruplexes cause eif4a-dependent oncogene translation in cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492470/
https://www.ncbi.nlm.nih.gov/pubmed/25079319
http://dx.doi.org/10.1038/nature13485
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