Review Translational control by oncogenic signaling pathways ☆ Beichen Gao a , Philippe P. Roux a,b, ⁎ a Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec, Canada b Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada abstract article info Article history: Received 7 September 2014 Received in revised form 17 November 2014 Accepted 19 November 2014 Available online xxxx Keywords: mRNA translation Cancer mTOR Protein synthesis mTORC1 MAPK Messenger RNA (mRNA) translation is highly regulated in cells and plays an integral role in the overall process of gene expression. The initiation phase of translation is considered to be the most rate-limiting and is often targeted by oncogenic signaling pathways to promote global protein synthesis and the selective translation of tumor-promoting mRNAs. Translational control is a crucial component of cancer development as it allows cancer cells to adapt to the altered metabolism that is generally associated with the tumor state. The phosphoinositide 3-kinase (PI3K)/Akt and Ras/mitogen-activated protein kinase (MAPK) pathways are strongly implicated in can- cer etiology, and they exert their biological effects by modulating both global and specific mRNA translation. In addition to having respective translational targets, these pathways also impinge on the mechanistic/mammalian target of rapamycin (mTOR), which acts as a critical signaling node linking nutrient sensing to the coordinated regulation of cellular metabolism. mTOR is best known as a central regulator of protein synthesis and has been implicated in an increasing number of pathological conditions, including cancer. In this article, we describe the current knowledge on the roles and regulation of mRNA translation by various oncogenic signaling pathways, as well as the relevance of these molecular mechanisms to human malignancies. This article is part of a Special Issue entitled: Translation and cancer. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Protein synthesis is a fundamental, but energy-costly [1], process that plays a major role in the post-transcriptional regulation of gene ex- pression [2]. A low concordance was observed between steady-state mRNA levels and the proteome [3,4], suggesting that translational con- trol plays a major role in overall gene expression. The process of mRNA translation is highly regulated in cells as it responds to local and system- ic changes in the cellular environment [5]. Many signaling pathways converge on components of the translational apparatus to regulate their function, particularly at the level of eukaryotic translation initia- tion factors (eIFs), such as eIF4E and eIF2α [2,6]. Translational control is a crucial component of cancer development and progression, as it di- rects both global protein synthesis and the selective translation of mRNAs involved in tumor cell growth, survival and proliferation [7–9]. Consistent with this, many components of the translational machinery were reported to be amplified or overexpressed in human malignancies, including eIF4E, eIF4G, eIF4A and several eIF3 isoforms (Table 1) [9]. Moreover, several oncogenes (PIK3CA, KRAS, MYC) and tumor suppres- sors (TP53, TSC2, PTEN) impinge on the translational machinery to con- trol global protein synthesis and specific mRNA translation [9,10]. For these reasons, intense efforts are currently being deployed to identify therapeutic agents that would target components of the translational machinery [11], and some of these have already shown anti-cancer ac- tivity in preclinical and early clinical trials [10]. In this article, we will re- view the role of the PI3K/mTOR and Ras/MAPK signaling pathways in the regulation of mRNA translation, especially with regard to their roles in tumorigenesis. 2. Cap-dependent mRNA translation initiation While mRNA translation occurs in three distinct stages (initiation, elongation and termination), most of the translational control is thought to occur at the rate-limiting initiation phase [2,6]. In eukaryotic cells, the vast majority of translation initiation events occur in a manner that is dependent on the 5′-terminal m 7 G[5′]ppp[5′]N-cap structure of mRNA (where N can be any nucleotide) [2,6,12]. Cap-independent mRNA translation, which can be mediated by an internal ribosome entry site (IRES) [13], also plays important roles in cancer [9,14,15], but this alternative mechanism of initiation will not be covered here. Biochimica et Biophysica Acta xxx (2013) xxx–xxx Abbreviations: eIF, eukaryotic initiation factor; eEF, eukaryotic elongation factor; 4E-BP, eIF4E-binding protein; TOP, terminal oligopyrimidine; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian/mechanistic target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; PDCD4, programmed cell death protein 4; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; Raptor, regulatory-associated protein of mTOR; Rictor, rapamycin-insensitive companion of mTOR; rp,ribosomal protein;S6K,p70 ribosomalS6kinase;MNK,MAPK-interacting kinase; RSK, p90 ribosomal S6 kinase ☆ This article is part of a Special Issue entitled: Translation and cancer. ⁎ Corresponding author at: Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec, Canada. Tel.: +1 514 343 6399; fax: +1 514 343 5839. E-mail address: philippe.roux@umontreal.ca (P.P. Roux). BBAGRM-00839; No. of pages: 13; 4C: 3, 4, 5, 8 http://dx.doi.org/10.1016/j.bbagrm.2014.11.006 1874-9399/© 2013 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagrm Please cite this article as: B. Gao, P.P. Roux, Translational control by oncogenic signaling pathways, Biochim. Biophys. Acta (2013), http:// dx.doi.org/10.1016/j.bbagrm.2014.11.006