Translational control by oncogenic signaling pathways.

BBAGRM-00839; No. of pages: 13; 4C: 3, 4, 5, 8 Biochimica et Biophysica Acta xxx (2013) xxx–xxx

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Review

Translational control by oncogenic signaling pathways☆ Beichen Gao a, Philippe P. Roux a,b,⁎ a b

Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec, Canada Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada

a r t i c l e

i n f o

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

a b s t r a c t 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 cancer 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 expression [2]. A low concordance was observed between steady-state mRNA levels and the proteome [3,4], suggesting that translational control plays a major role in overall gene expression. The process of mRNA translation is highly regulated in cells as it responds to local and systemic 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 initiation factors (eIFs), such as eIF4E and eIF2α [2,6]. Translational control is a crucial component of cancer development and progression, as it directs both global protein synthesis and the selective translation of 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 ribosomal S6kinase; 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: [email protected] (P.P. Roux).

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 suppressors (TP53, TSC2, PTEN) impinge on the translational machinery to control 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 activity in preclinical and early clinical trials [10]. In this article, we will review 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 m7G[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.

http://dx.doi.org/10.1016/j.bbagrm.2014.11.006 1874-9399/© 2013 Elsevier B.V. All rights reserved.

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

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B. Gao, P.P. Roux / Biochimica et Biophysica Acta xxx (2013) xxx–xxx

Table 1 Translation initiation factors and their dysregulation in cancer. Initiation factor

No. of subunits

Function

Link to cancer

eIF1

1

?

eIF1A

1

eIF2

eIF4B eIF4E

3 (α, β, γ) 5 (1–5) 13 (A–M) 3 (1–3) 1 1

Start codon (AUG) scanning and recruitment of TC to 40S subunits, prevents premature eIF2-bound GTP hydrolysis by eIF5 Stimulates binding of the TC to 40S subunits, and cooperate with eIF1 in AUG scanning and codon selection Forms an eIF2-GTP-Met-tRNA TC that binds to 40S subunits

eIF5

eIF4G eIF4H eIF5

(1–2) 1 1

Increases eIF4A activity, and binds to eIF4E, eIF4A, eIF3, PABP and mRNA Promotes eIF4A helicase activity GAP that hydrolyses GTP-bound eIF2 upon identification of the start codon

eIF6

eIF5B eIF6

1 1

Catalyses 60S joining to the 48S initiation complex Binds 60S ribosomal subunits to prevent 80S formation

eIF1

eIF2

eIF2B eIF3

eIF3

eIF4

eIF4A

GEF that promotes GDP–GTP exchange on eIF2 Binds eIF1, eIF4, eIF5 and 40S subunits to stabilize the translational complex. Promotes mRNA recruitment to 43S subunits DEAD-box RNA helicase that unwinds secondary structures in mRNA 5′ UTR Promotes eIF4A helicase activity Binds to the 5′ cap structure of mRNA and interacts with eIF4G

? Overexpressed in many cancers, including lymphomas [228] ? Overexpressed in many cancers, including breast and prostate [229] Overexpressed in many cancers, including lung and cervical [230,231] Overexpressed in B-cell lymphoma [232] Overexpressed in many cancers, including breast and head and neck [233,234] Overexpressed in breast cancer [15] ? Overexpressed in many cancers, including colorectal [235] ? ?

TC, ternary complex; GEF, guanine nucleotide exchange factor; GAP, GTPase-activating protein.

During cap-dependent translation, the eIF4F complex is recruited to the m7G-cap structure of all nuclear-encoded mRNAs [16]. The heterotrimeric eIF4F complex contains a scaffold protein (eIF4G), a DEAD (Asp-Glu-Ala-Asp)-box RNA helicase (eIF4A) and the capbinding protein eIF4E [17], which are involved in the recruitment of the ribosome to the mRNA [2,6]. Whereas eIF4E binds directly to the m7G-cap structure, eIF4G interacts with several additional protein partners, including eIF4E, eIF4A, eIF3, and the poly(A)-binding protein (PABP, also known as PABPC1) [18]. eIF3 is a large multisubunit protein complex that facilitates the recruitment of the 40S ribosomal subunit to the 5′ end of mRNA [19,20]. PABP attaches to both the 3′ poly(A) tail and eIF4G, bringing both ends of the mRNA together to stabilize the transcript and augment translation [21,22]. The primary function of eIF4A is to facilitate scanning of the 40S subunit towards the initiation codon by resolving the secondary structures in the 5′ untranslated region (5′ UTR) of the mRNA [23–25]. The activity of eIF4A is stimulated by its association with the eIF4F complex [24], but also via the recruitment of the accessory factors eIF4B and eIF4H [26]. Recognition of the initiation codon by the 40S ribosomal subunit leads to the recruitment of the 60S ribosomal subunit to form a translation-competent 80S ribosome [2,6]. 2.1. Translational control at the level of eIF2α A major mechanism of translational control involves phosphorylation of the α subunit of eIF2 [2,6], which is mediated by several stressactivated protein kinases [27]. The main role of eIF2 is to deliver initiator methionyl tRNA (Met-tRNAi) to the translational machinery in the form of a ternary complex (TC). Phosphorylation of eIF2α on Ser51 converts eIF2-GDP into a competitive inhibitor of the multisubunit GEF (guanine nucleotide exchange factor) eIF2B, resulting in decreased TC assembly and translation initiation [28]. To date, four eIF2α kinases have been identified, including PKR (interferon-induced, double-stranded RNAactivated protein kinase), PERK (PKR-like ER kinase), GCN2 (general control non-derepressible-2) and HRI (heme-regulated inhibitor) [27]. These protein kinases inhibit mRNA translation in response to a wide array of cellular stresses, such as viral infection, amino acid deficiency, and the accumulation of unfolded proteins [27]. In addition to reducing general translation initiation, phosphorylation of eIF2α paradoxically induces the translation of stress-induced mRNAs harboring short, upstream open reading frames (uORFs) [25]. These mRNAs encode various transcriptional regulators, such as GCN2 and ATF4, which facilitates the

expression of genes involved in the integrated stress response [28]. Whether eIF2α phosphorylation stimulates or prevents cancer development is a complex issue that might be context-dependent and vary based on the stage and grade of the disease [9,29]. 2.2. Translational control at the level of eIF4E A second important mechanism of translational control involves the eIF4E-binding proteins (4E-BPs), which inhibit cap-dependent translation by preventing eIF4F complex assembly [30,31]. In mammals, there are three 4E-BP isoforms (4E-BP1, 2 and 3) which compete with eIF4G for a shared binding site on the dorsal surface of eIF4E [32]. New findings indicate that the 4E-BPs can also interact with the lateral surface of eIF4E, which may help in the displacement of eIF4G from the dorsal surface of eIF4E [33]. Because of their mechanism of action involving eIF4E binding, the 4E-BPs have little effect on IRES-dependent translation which is cap-independent. The 4E-BPs have been shown to play important roles in the control of cell proliferation [34], and consistent with this, their reduced expression correlates with poor patient survival [35]. An important mechanism of 4E-BP regulation is through phosphorylation, which alters their ability to interact with eIF4E. Whereas hypophosphorylated 4E-BPs strongly associate with eIF4E, phosphorylation of the 4E-BPs on multiple residues weakens their interaction with eIF4E [31]. High levels of phosphorylated 4E-BP1, which usually correlates with increased eIF4F assembly, were found in different malignancies, including breast, colorectal and prostate cancers [9,36]. Phosphorylation of the 4E-BPs is thought to be mainly regulated by mammalian/mechanistic target of rapamycin (mTOR), which is an important regulator of protein synthesis. mTOR phosphorylates the 4E-BPs on several residues in a hierarchal manner, and thereby facilitates eIF4F complex assembly at the 5′ end of mRNA [37,38]. Additional protein kinases were shown to regulate the phosphorylation of the 4E-BPs, including GSK3β and CK1ε [39,40], but the relevance of these proteins in the regulation of cap-dependent translation remains to be fully characterized. 3. Cap-dependent translation in cancer Initiation is the rate-limiting phase of translation [2,6], and as such, cancer cells have devised numerous ways to promote cap-dependent translation in the absence of growth signals. Indeed, the assembly and activity of the eIF4F complex is tightly regulated by signaling pathways



that are involved in cancer development and progression. These pathways include the PI3K/mTOR and Ras/MAPK signaling cascades [5,8], which will be discussed in more detail below. In addition, several eIFs have been shown to be overexpressed in cancer, one such example is eIF4E whose overexpression correlates with poor clinical outcome in breast, head and neck, colorectal, liver, lung, prostate and bladder cancers [8,9,41,42]. Early studies showed that immortalized murine NIH-3T3 cells could be transformed by overexpression of eIF4E [43], and subsequent work demonstrated that eIF4E overexpression in mouse models promotes B cell lymphomas, angiosarcomas, hepatocellular carcinomas and lung adenocarcinomas [9,44]. The increased abundance of eIF4E may promote protein synthesis at a global scale, by increasing the availability of assembled eIF4F complexes, but also

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facilitates the translation of transcripts that are more dependent on the presence of eIF4E [45]. The other two components of the eIF4F complex have also been shown to be overexpressed in certain cancers. Increased expression of eIF4G was reported in cancers of the lung, breast and cervix, and is globally associated with poor patient outcomes [9]. Similar to eIF4E, eIF4G overexpression was shown to have transforming activity in NIH-3T3 cells and to increase the growth of tumor xenografts in nude mice [46]. Because of its ability to bind IRES sequences and thereby recruit 40S ribosomal subunits, transformation mediated by eIF4G might also result from its ability to drive the capindependent translation of mRNAs involved in the stress response, angiogenesis and survival [14,15]. Overexpression of the RNA helicase eIF4A has also been reported in lung, liver and cervical cancers, as well

Fig. 1. Expression profile of translation factors in breast, colorectal, lung and prostate tumors. RNA-Seq data from The Cancer Genome Atlas (TCGA) was analyzed for the expression levels of all translation initiation factors, as well as the 4E-BPs and PABP. A gene was considered as being up- or down-regulated when its expression value was two standard deviations away from the mean of expression within normal tissues (z-score threshold of 2). The number expressed as a percentage indicates the proportion of tumors (from the total number indicated) that have increased (green) or decreased (red) levels of the indicated mRNAs compared to normal tissues.


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as in melanomas [9]. Overexpression of eIF4A likely contributes to the elevated helicase activity associated with the eIF4F complex at the 5′ end of mRNA, and subsequently to the increased translation of transcripts with structured 5′ UTRs. Using RNA Sequencing (RNA-Seq) data from The Cancer Genome Atlas (TCGA), we analyzed the mRNA expression profile of all translation initiation factors, as well as the 4E-BPs and PABP (Fig. 1). In this exercise, a large number of breast, colorectal, lung and prostate tumors were analyzed, which are four of the most frequent types of cancer [47,48]. For the purpose of this analysis, a gene was considered as being up- or down-regulated when its expression value was two standard deviations away from the mean of expression in normal tissues (z-score threshold of 2). Overall, we did not detect any major trends in mRNA downregulation across these four cancers. While it is possible that certain translation factors are downregulated in a post-transcriptional manner, these data suggest that none of these genes are negatively regulated at the transcriptional level. Interestingly, we found that many factors were upregulated across cancer types, including mRNAs encoding for eIF2β, eIF3B, eIF3E, eIF3H and PABP (Fig. 1). Some translation factors appeared to be specifically upregulated in certain cancer types. For example, ~50% of colorectal tumors were found to have an upregulation in the mRNAs encoding for eIF2β and eIF6, whereas several factors appeared to be upregulated in lung tumors, including eIF3B (29% of tumors), eIF3D (17%), eIF3G (18%), eIF3H (23%), eIF3K (20%), and PABP (24%). Overall, these data indicate that the elevation in protein synthesis seen in cancer cells likely involves the overexpression of components of the translational apparatus.

4. The mammalian/mechanistic target of rapamycin (mTOR) mTOR is an evolutionarily conserved Ser/Thr kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family [49]. It has emerged as a critical node through which cells coordinate growth and proliferation in response to both intracellular and extracellular cues [50]. Deregulation of mTOR signaling is implicated in the development of several human diseases, including cancer, type 2 diabetes and obesity [51]. As such, intense efforts are currently being deployed to determine the therapeutic impact of inhibiting mTOR activity in different types of malignancies [11]. mTOR forms the catalytic core of at least two functionally distinct complexes known as mTOR complex 1 (mTORC1) and complex 2 (mTORC2), which regulate different cellular functions by phosphorylating different sets of protein substrates (Fig. 2) [51].

mTORC1 regulates many cellular processes associated with cell growth and proliferation, including mRNA translation, ribosome biogenesis and autophagy [52]. mTORC2 phosphorylates several AGC kinases, including Akt, PKC and SGK1, and thereby regulates cell survival and cytoskeletal organization [53–56]. mTORC2 was also reported to associate with the ribosome in response to growth factors [57], where it phosphorylates residues in nascent polypeptide chains that contribute to proper protein folding [58]. mTORC1 and mTORC2 contain shared protein partners, including mTOR, mLST8 (mammalian lethal with Sec13 protein 8) and Deptor (DEP-domain-containing mTOR-interacting protein) [52]. While mLST8 appears more critical for mTORC2 assembly and signaling [59], Deptor was described as an inhibitor of both complexes [60]. Both mTORC1 and mTORC2 contain specific components, such as Raptor (regulatory-associated protein of mTOR) and Rictor (rapamycin-insensitive companion of mTOR), respectively [61]. Both of these proteins appear to serve as scaffolding elements that facilitate the recruitment of regulators and substrates to mTOR, which in the case of Raptor, was shown to depend on a TOR-signaling (TOS) motif in binding proteins [62,63]. 4.1. Pharmacological inhibition of mTOR in cancer mTOR is the functional target of the natural macrolide rapamycin (clinically known as sirolimus). The mechanism of action of rapamycin involves its association with the cellular protein FKBP12, which then interacts with the FRB (FKBP12-rapamycin binding) domain of mTOR. mTORC1 and mTORC2 are differentially sensitive to rapamycin, as the latter was shown to be resistant to acute drug treatments [64,65]. mTORC2 can be inhibited by prolonged rapamycin treatment, likely by impeding its assembly in a cell type-specific manner [65]. Although the mechanism by which rapamycin inhibits mTORC1 signaling is not well defined, binding of the rapamycin:FKBP12 complex was shown to weaken the interaction between mTOR and Raptor, and partially reduce mTORC1 catalytic activity [66,67]. Recent studies have revealed that mTORC1 inhibition by rapamycin is incomplete; rapamycin was found to efficiently suppress the phosphorylation of some mTORC1 substrates (e.g., S6Ks), but not others (e.g., 4E-BPs) [68–70]. Since these findings, several catalytic inhibitors of mTOR have been identified and found to have more potent activity than rapamycin [64,71,72]. Surprisingly, these compounds were found to inhibit cell growth and proliferation largely independently of mTORC2, suggesting that they likely target rapamycin-resistant functions of mTORC1 [71]. The mTOR kinase domain is highly related to that of PI3K, explaining why several catalytic inhibitors of mTOR also target the latter [71].

Fig. 2. The mTORC1 and mTORC2 complexes. The mTOR kinase nucleates two distinct protein complexes in cells, termed mTORC1 and mTORC2. Whereas mTOR, Deptor and mLST8 are shared by both complexes, mTORC1 and mTORC2 are also composed of specific components. While Raptor and PRAS40 are specific to mTORC1, Rictor, mSin1 and Protor1/2 are only found in mTORC2. mTORC1 responds to growth factors, nutrients and diverse cellular stresses to promote cell growth by inducing and inhibiting anabolic and catabolic processes, respectively. mTORC2 responds to growth factors and regulates cell survival and metabolism, as well as the actin cytoskeleton.



Preclinical studies have revealed that the new generation of mTOR inhibitors potently inhibits cancer cell growth and proliferation in vitro, as well as the development of tumors in animal models, thereby showing stronger overall efficacy than rapamycin and its analogs [73–75]. mTOR activity was shown to be deregulated in a large number of malignancies, including breast and endometrial cancer, as well as in nonHodgkin lymphoma and advanced stages of solid tumors [71]. Many catalytic inhibitors of mTOR are currently in phase I clinical trials, and are being tested as single agents or in combination with conventional chemotherapeutics [72]. 5. Upstream regulation of mTORC1 activity mTORC1 regulates protein synthesis in response to many types of signals, including growth factors, nutrients, glucose and oxygen (Fig. 3) [76]. These factors regulate mTORC1 signaling through multiple mechanisms, particularly at the level of the small GTPases Rheb (Rashomolog enriched in brain) and Rag (Ras-related GTP-binding protein) which regulate mTORC1 subcellular localization and activity [77]. 5.1. Growth factor signaling to the Rheb GTPases The tumor suppressor TSC (tuberous sclerosis complex), which is composed of TSC1 (hamartin), TSC2 (tuberin) and TBC1D7 (Tre2-Bub2-

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Cdc16 [TBC] 1 domain family member 7), integrates diverse regulatory signals to suppress mTORC1 function (Fig. 3) [50]. Tuberous sclerosis is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes and is associated with hamartoma formation in multiple organ systems [78]. Although germline mutations in TBC1D7 have not yet been identified in TSC patients, homozygous disruption of TBC1D7 was found to cause intellectual disabilities and megalencephaly [79–81]. While the loss of TBC1D7 was associated with increased mTORC1 signaling, affected patients did not show any specific features of TSC [80]. The TSC complex negatively regulates mTORC1 by functioning as a GTPase-activating protein (GAP) for Rheb, which is a positive regulator of mTORC1 activity [82,83]. Growth factors and hormones stimulate mTORC1 activity via two well-characterized signaling cascades, the PI3K/Akt and Ras/MAPK pathways, which converge on TSC to inhibit its function [84,85]. Both of these pathways activate mTORC1 primarily by phosphorylating TSC2 and thereby suppressing the inhibitory effect of the TSC complex on Rheb activity [86–91]. Upon stimulation with growth factors, the GTP-bound form of Rheb accumulates and directly activates mTORC1. While Rheb-GTP was shown to directly interact with the mTOR kinase domain [92], the molecular mechanisms by which Rheb activates mTORC1 remain ill-defined. Several components of the PI3K/Akt and Ras/MAPK pathways are oncogenes or tumor suppressors, which is consistent with the observation

Fig. 3. Schematic representation of mTORC1 signaling to the translational machinery. Growth factors stimulate mTORC1 by activating a receptor tyrosine kinase (RTK) at the cell surface, which promotes signaling via the PI3K/Akt and Ras/MAPK pathways. mTORC1 is also activated by amino acids via the Rag GTPases. Conversely, insufficient energy resources, hypoxia and DNA damage inactivate mTORC1 via specific regulatory pathways. mTORC1 modulates mRNA translation via the phosphorylation of its downstream targets, which include the 4E-BPs and S6Ks. In addition, mTORC1 stimulates ribosome biogenesis and tRNA synthesis by activating TIF-1A and inhibiting Maf1, respectively. T-bars represent inhibitory signals, whereas arrows indicate stimulatory signals.


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that mTORC1 activity is frequently upregulated in human malignancies [36,93]. In addition to regulating TSC function, growth factors stimulate mTORC1 activity by directly modifying mTORC1 components. For example, Akt and mTORC1 phosphorylate and negatively regulate PRAS40 (Akt/PKB substrate 40 kDa), which interacts with Raptor and acts as an inhibitory partner of mTORC1 [94–97]. In addition, activation of the Ras/MAPK pathway was shown to promote ERK1/2 (extracellular signal-regulated kinases 1 and 2)- and RSK (p90 ribosomal S6 kinase)dependent phosphorylation of Raptor, which correlates with increased mTORC1 signaling to downstream substrates [98,99]. A recent report also indicated that RSK phosphorylates Deptor and thereby promotes its proteosomal degradation [100], suggesting an additional means of regulating mTOR signaling by this pathway. 5.2. Amino acid sensing at the lysosome by the Rag GTPases mTORC1 activity depends on amino acid sufficiency, particularly leucine, arginine and glutamine [101–103]. The mechanisms by which mTORC1 senses amino acids are poorly known, but recent findings indicate that the localization of mTORC1 at the lysosome is critical for this process (Fig. 3) [104]. While the lysosomal recruitment of mTORC1 is not sufficient to activate the complex, it is believed to be a mechanism that brings mTORC1 in proximity to its upstream activator Rheb, which resides in this compartment [105]. mTORC1 regulation by amino acids involves a large number of proteins that ultimately regulate the activity of the Rag GTPases. These evolutionarily conserved proteins function as obligate heterodimers in which RagA or RagB interacts with RagC or RagD [106]. In the presence of amino acids, Rag heterodimers adopt their active configuration (RagA/B bound to GTP, and RagC/D bound to GDP) and interact with Raptor to recruit mTORC1 to the lysosome [105,107]. This change in localization ensures that mTORC1 activation occurs only when growth conditions are optimal (i.e., during nutrient sufficiency and in the presence of growth factors). Two protein complexes have been shown to regulate the activity of the Rag GTPases, the Ragulator (consisting of p14, p18, MP1, c7orf59 and HBXIP) and GATOR1 (consisting of DEPDC5, Nprl2 and Nprl3), which act as GEF and GAP towards RagA/B, respectively [108,109]. While the Ragulator tethers the Rag GTPases to the lysosome in addition to enabling the exchange of GDP to GTP on RagA/B, GATOR1 stimulates the intrinsic GTPase activity of RagA/B leading to mTORC1 inhibition [109,110]. Inhibition of GATOR1 activity was shown to promote mTORC1 signaling, and consistent with this, components of GATOR1 are frequently mutated in human cancers [109]. The GATOR1 complex is itself subject to regulation by another protein complex known as GATOR2 (consisting of Mios, WDR24, WDR59, Seh1L and Sec13), whose inactivation suppresses mTORC1 signaling [109]. In addition to these mechanisms, a protein called folliculin (FLCN) was shown to have GAP activity towards RagC/D and to be a positive regulator of mTORC1 signaling [111,112]. The recruitment of mTORC1 to Rag GTPases requires RagC/D to be GDP bound, which appears to be regulated by FLCN and its binding partners, FNIP1/2. How the Ragulator complex senses amino acids remains largely unknown, but the vacuolar (H+)-ATPase (v-ATPase) was shown to play some roles in this process [52]. The membrane-spanning v-ATPase is thought to sense intra-lysosomal amino acids and relay this signal using an “inside-out” mechanism to the Ragulator complex on the cytosolic face of the lysosome [52]. While mTORC1 activity is controlled by amino acids via its recruitment at the lysosome by the Rag GTPases, growth factors were shown to relocate the TSC complex away from the lysosome to promote Rheb-dependent stimulation of mTORC1 signaling [113,114]. 5.3. Energy and stress sensing mTORC1 activity is sensitive to diverse forms of stress, such as glucose deprivation, hypoxia, or pharmacological inhibition of mitochondrial

function, which result in reduced cellular ATP levels [77]. Energy stress inhibits mTORC1 signaling via AMPK (AMP-activated protein kinase), which is a multisubunit sensor of the nutritional status of the cell (Fig. 3) [115,116]. In response to conditions that increase the intracellular AMP/ATP ratio, AMPK binds AMP and becomes phosphorylated by its upstream activator, the protein kinase LKB1 (liver kinase B1) [115]. This regulation was recently shown to take place at the late endosome/ lysosome in response to glucose starvation, where the v-ATPaseRagulator complex recruits LKB1 bound to the scaffold protein AXIN [117]. Once activated, AMPK phosphorylates TSC2 and promotes its inhibitory action against Rheb and mTORC1 [118]. AMPK was also shown to inhibit mTORC1 signaling in a TSC2-independent manner, involving the phosphorylation of Raptor on sites that promote the recruitment of 14–3–3 proteins [119]. Inhibition of mTORC1 signaling was shown to be required for the block in proliferation exerted by AMPK [119], suggesting that AMPK mediates its effects in part by inhibiting mTORC1dependent protein synthesis. Independent of cellular ATP levels, hypoxia represses mTORC1 signaling by upregulating REDD1 (regulated in development and DNA damage responses 1) in a HIF-1 (hypoxia-inducible factor 1)-dependent manner [120]. The role of mTORC1 in the regulation of HIF-1α was recently shown to involve multiple mechanisms, including both translational and transcriptional gene regulation [121]. Although the exact mechanisms are poorly known, REDD1 was shown to inhibit mTORC1 activity by converging on the TSC complex and destabilizing it [120, 122]. In addition to hypoxia and glucose deprivation, REDD1 expression was shown to be induced by endoplasmic reticulum (ER) stress in an ATF4-dependent manner [123], thereby restraining mTORC1 signaling and protein synthesis. mTORC1 activity was also shown to be inhibited by genotoxic stress that activates the tumor suppressor p53 and upregulates its target genes, such as the sestrins [124]. Sestrin 1 and 2 were shown to activate AMPK and promote TSC2 phosphorylation at AMPK-dependent sites, thereby increasing its GAP activity towards Rheb [124]. Like the sestrins, REDD1 expression was also shown to partly depend on p53 activity, suggesting its potential role in response to genotoxic stress [125]. 6. mTORC1 signaling to the translation machinery The presence of growth factors and the sufficiency in nutrients stimulates mTORC1 signaling to its downstream substrates, which include the eIF4E-binding proteins (4E-BPs) and the p70 ribosomal S6 kinases (S6Ks) (Fig. 3). Although the mTORC1-dependent phosphoproteome was shown to include a large number of potential substrates [126,127], the 4E-BPs and S6Ks represent the most extensively studied and bestunderstood downstream effectors of mTORC1 involved in the regulation of mRNA translation. 6.1. The eIF4E-binding proteins (4E-BPs) Regulation of the mRNA cap-binding protein eIF4E is directly mediated by mTORC1, which phosphorylates its inhibitors, the 4E-BPs [128]. The 4E-BPs are small translational repressors (4E-BP1, 2 and 3 in mammals) that interfere with eIF4F assembly at the 5′ end of mRNA by competing with eIF4G for binding to eIF4E [31]. Upon activation, mTORC1 phosphorylates residues corresponding to Thr37 and Thr46 on human 4E-BP1, which act as priming sites for the subsequent phosphorylation of Ser65 and Thr70 [37,38]. Phosphorylation of the 4E-BPs on these four residues leads to their dissociation from eIF4E, thus allowing eIF4F assembly and cap-dependent translation [31,37,38]. While eIF4E is globally required for cap-dependent translation, some transcripts appear to be particularly dependent on eIF4E for their translation, such as those containing relatively long and structured 5′ UTRs (also referred to as “eIF4E-sensitive” mRNAs) [45]. eIF4E is the most limiting subunit of the eIF4F complex, and its availability strongly determines translational activity of these mRNAs [2]. Alterations in the



expression and/or the phosphorylation status of the 4E-BPs only marginally affect global protein synthesis, while strongly influencing translation of eIF4E-sensitive transcripts (e.g., IRF-7, Gas2, cyclin D3, ornithine decarboxylase [ODC] and VEGF) [34,129–131]. When eIF4E is less abundant, mRNAs with short and unstructured 5′ UTRs are favored for translation, such as those encoding housekeeping mRNAs (e.g., GAPDH and β-actin). Conversely, eIF4E overexpression is thought to increase the levels of available eIF4F complex, which enables translation of mRNAs with long or highly structured 5′ UTRs [9,45,132]. The eIF4E-sensitive transcripts frequently encode proteins involved in cell survival and proliferation [34], such as cyclins [133], ODC [134], VEGF [135] and Myc [136], which probably explains why eIF4E is overexpressed in many types of cancer [9]. Recently, another subset of mRNAs encoding proteins involved in mitochondrial function and biogenesis has been shown to be sensitive to eIF4E [137], but these do not appear to have particularly structured 5′ UTRs and thus the mechanism responsible for their sensitivity to eIF4E levels remains unknown. In addition to its effects on global protein synthesis, mTORC1 selectively stimulates translation of “eIF4E-sensitive” mRNAs by phosphorylating and inactivating the 4E-BPs, thereby mediating the effects of mTORC1 on cell proliferation [34]. 6.2. The p70 ribosomal S6 kinases (S6Ks) Other important targets of mTORC1 in translational control include the S6Ks (S6K1 and S6K2), which are important growth regulators downstream of mTORC1 (Fig. 3) [34,138,139]. Results from mouse knockouts and from RNA interference studies reveal both redundant and isoform-specific functions for the S6Ks [140]. In particular, S6K1, but not S6K2, seems to contribute more significantly to the ability of mTORC1 to regulate cell growth [141]. S6K1 and S6K2 exist in two different isoforms (p70/p85 for S6K1, and p54/p56 for S6K2), which result from alternative translational initiation sites in a common mRNA [142,143]. Whereas the p70 isoform of S6K1 is predominantly cytoplasmic, the p85 isoform of S6K1 and both p54/p56 isoforms of S6K2 are mostly localized in the nucleus [144]. The S6Ks are activated by PDK1 (phosphoinositide-dependent kinase 1) and mTORC1 via the phosphorylation of their activation loop (Thr229 in human S6K1) and hydrophobic motif (Thr389 in human S6K1), respectively [144]. S6K1 activation is initiated by phosphorylation of Thr389 by mTORC1, which creates a docking site for PDK1 [145]. Upon recruitment, PDK1 phosphorylates S6K1 on Thr229 and thereby stimulates the activity of its kinase domain [140]. Recent findings indicate that GSK3 phosphorylates S6K1 at its turn motif (Ser371 in human S6K1), which is critical for subsequent phosphorylation at Thr389 and for S6K1 activity [146]. A principal function of the S6Ks is to coordinate ribosome biogenesis, which in turn increases the overall protein biosynthetic capacity of the cell [147]. Specifically, the S6Ks were found to promote the transcription of genes involved in the ribosome biogenesis (RiBi) transcriptional program, which include many nucleolar factors required for ribosomal RNA (rRNA) synthesis, cleavage, post-transcriptional modifications, assembly with ribosomal proteins (RPs) and transport [148]. While the exact molecular mechanisms are not well understood, phosphorylation of ribosomal protein S6 (rpS6) was found to affect RiBi transcription [148]. rpS6 was the first identified S6K substrate [149,150], and is phosphorylated at its C-terminus on five residues (Ser235, Ser236, Ser240, Ser244, and Ser247 in human rpS6) [151]. A direct function for rpS6 phosphorylation in translational control is lacking, but experiments using mice in which rpS6 is replaced by a non-phosphorylatable mutant revealed that the loss of rpS6 phosphorylation results in reduced RiBi transcription [148]. How phosphorylated rpS6 may affect RiBi transcription is unknown, but there are precedents for other ribosomal proteins affecting mRNA metabolism or gene transcription [152,153]. The S6Ks promote ribosome biogenesis via additional mechanisms, including the Pol I-specific factor UBF (upstream-binding factor) [154]. S6K1 phosphorylates UBF in its C-terminal region, and this phosphorylation is required

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for the interaction between UBF and transcription initiation factor (TIF) IB (SL1) [155,156]. Whereas mTOR was shown to play an important role in the translation of mRNAs encoding ribosomal proteins and certain initiation factors (collectively called terminal oligopyrimidine [TOP] mRNAs), the S6Ks do not appear to play a role in this process [139,157]. Rather, a protein termed La-related protein 1 (LARP1) was recently found to be regulated by mTORC1 and to regulate TOP mRNA translation [158]. Although the S6Ks play essential roles in the regulation of ribosome biogenesis, accumulating evidence suggests that these proteins also modulate translation initiation in response to mTORC1 activation. Several phosphorylation substrates of the S6Ks have been implicated in translational control, including programmed cell death 4 protein (PDCD4) [159] and eukaryotic initiation factor 4B (eIF4B) [160,161]. PDCD4 is a tumor suppressor that binds to eIF4A and thereby competes with eIF4G to inhibit translation initiation [162,163]. The S6Ks were shown to phosphorylate PDCD4 on both Ser67 and Ser457, leading to its degradation by the E3 ubiquitin ligase SCFβTrCP1 [159]. More recently, the related RSK protein kinases were also shown to phosphorylate PDCD4 on a different pair of residues (Ser76 and Ser457), which resulted in 14–3–3 recruitment and PDCD4 degradation [164]. It appears, therefore, that the degradation of PDCD4 and subsequent release of eIF4A are important events in cellular response to growth factors. In addition to PDCD4, the S6Ks phosphorylate eIF4B at residues that appear to promote its recruitment to eIF3 within translation initiation complexes [165]. eIF4B is an auxiliary factor that stimulates the RNA unwinding activity of eIF4A [23,31,166–168]. It appears, therefore, that eIF4B phosphorylation stimulates the translation of mRNAs containing highly structured 5′ UTRs, such as those encoding Cdc25, ODC, XIAP and Bcl-2 [169]. Again, eIF4B was shown to be regulated by additional AGC kinases, such as RSK (Ser406 and Ser422) and Akt (Ser422) in a stimulus- and cell type-dependent manner [160,161,170]. It was suggested that eIF4B phosphorylation also promotes its association with eIF3 [161,165], which may be an additional point of contact within the translation initiation complex. Another important substrate of S6Ks is the eukaryotic elongation factor 2 (eEF2) kinase, which negatively regulates translation elongation by phosphorylating and inhibiting eEF2 [171]. This inhibition is relieved when eEF2 kinase is phosphorylated at Ser366 by S6K1 or RSK [172]. Finally, S6K1 has been shown to facilitate the translation of newly spliced mRNAs upon its recruitment to the exon-junction complex (EJC) by its substrate and binding partner SKAR (S6K1 Aly/REFlike target) [173]. Recruitment of S6K1 and SKAR to the EJC leads to the phosphorylation of numerous mRNA binding proteins and correlates with the increased translational efficiency of spliced mRNAs [174]. 6.3. Additional mTORC1 targets implicated in mRNA translation eIF4G is a modular scaffold that plays a critical role in the recruitment of the translational machinery to the mRNA and has been shown to be upregulated in a number of human malignancies [18]. In response to serum stimulation, eIF4G becomes phosphorylated on multiple residues in a manner that is dependent on mTORC1 [175], but the function of these phosphorylation events remains unknown. mTOR also stimulates ribosome biogenesis in a manner that is independent of the S6Ks [176], including the direct phosphorylation of TIF-1A [177] and Maf1 [178], which regulate Pol I and Pol III activity, respectively. 7. MAPK signaling to the translational machinery The MAPKs are evolutionarily conserved Ser/Thr kinases that regulate a wide array of biological functions and processes, including gene expression, mitosis, metabolism, motility, survival, apoptosis, and differentiation [179]. In mammals, 14 MAPKs have been characterized into seven groups, but the most extensively studied MAPKs are the


8


ERK1/2, JNKs, and p38 isoforms [180–182]. The different functions regulated by these MAPKs are mediated through phosphorylation of many substrates, including members of a family of Ser/Thr kinases termed MAPK-activated protein kinase (MAPKAPK) [183–185]. Two MAPKAPKs have been directly implicated in the regulation of mRNA translation (Fig. 4), namely the RSKs [186] and the MAPK-interacting kinases (MNKs) [187]. While mitogens and growth factors stimulate the RSK isoforms in response to ERK1/2 activation, the MNKs are activated by both mitogenic and stress stimuli in response to ERK1/2 and p38 isoforms [183]. The RSKs and MNKs are activated by their respective MAPKs upon phosphorylation of a residue within the activation loop of their kinase domain [188]. 7.1. The MAPK-interacting kinases (MNKs) Whereas mTORC1 regulates eIF4E function by phosphorylating the 4E-BPs, eIF4E itself is directly phosphorylated at Ser209 (in human eIF4E) by MNK1 and MNK2 [189,190]. Both the Mnk1 and Mnk2 genes generate two spliced isoforms, a long form (MNK1A and MNK2A) and a short one (MNK1B and MNK2B) that lacks the C-terminal MAPKbinding motif [191,192]. In most cell lines, MNK2A displays high basal activity which correlates with its ability to constitutively interact with activated ERK1/2 [187]. Conversely, MNK1A was shown to have low basal activity which can be stimulated by both ERK1/2 and p38 MAPKs in response to diverse stimuli [193]. Whereas MNK1A and MNK2A have a predominantly cytoplasmic localization, MNK1B and MNK2B appear to be equally distributed between the nucleus and the cytoplasm [187]. Both MNK1 and MNK2 contain a polybasic sequence that lies N-terminal to the kinase domain, which is involved in the recognition

of eIF4G [194]. This binding was found to be necessary for MNKdependent phosphorylation of eIF4E at Ser209 in response to stress and mitogen stimulation (Fig. 4) [189,193,195]. Whereas eIF4E phosphorylation was initially shown to be required for normal development in Drosophila [196], Mnk1 and Mnk2 double knockout (DKO) mice or mice in which wild-type eIF4E was replaced with a non-phosphorylatable mutant (S209A) do not exhibit any obvious phenotype [197,198]. While the molecular function of eIF4E phosphorylation is still unknown, it appears to require eIF4F formation as the MNKs are recruited to the complex through an interaction with eIF4G [194]. It was initially predicted that phosphorylation of Ser209 may stabilize eIF4E binding to the 5′ mRNA cap structure [199,200]. However, subsequent studies revealed that eIF4E phosphorylation reduces its affinity for the cap [201,202]. Consistent with these discrepancies, eIF4E phosphorylation was shown to correlate with both increased [203–206] or decreased global mRNA translation rates [195,207,208], and a clear consensus has yet to emerge. While the exact role of eIF4E phosphorylation on global translation rates remains unknown, phosphorylation of Ser209 appears to contribute to the tumorigenic activity of eIF4E [209]. Indeed, expression of the S209A mutant of eIF4E was shown to inhibit cancer cell proliferation in vitro and reduce the oncogenic potential or eIF4E in vivo [210,211]. Consistent with these findings, eIF4E phosphorylation was found to positively correlate with prostate cancer progression [198]. Phosphorylated eIF4E was suggested to promote tumorigenesis primarily by suppressing apoptosis and, accordingly, the anti-apoptotic protein Mcl-1 was found to be differentially translated depending on the phosphorylation status of eIF4E [210]. eIF4E phosphorylation was also shown to be particularly important for the translation of mRNAs encoding inflammatory molecules (Ccl2 and Ccl7) and matrix metalloproteases (MMP3

Fig. 4. Schematic representation of MAPK signaling to the translational machinery. The Ras/MAPK and p38 MAPK pathways regulate the translational machinery at different levels. While Ras/MAPK signaling stimulates the activity of both RSK and MNK, the latter is also responsive to agonists of the p38 MAPKs. MNK1/2 interacts with eIF4G and upon activation by either ERK1/2 or p38 MAPKs, phosphorylates eIF4E at Ser209, a site that increases its oncogenic potential and facilitates the translation of specific mRNAs. Following stimulation of the Ras/MAPK pathway, activated RSK phosphorylates several targets involved in translational regulation. RSK also participates in the regulation of mTORC1 by inhibiting the TSC complex, which is a negative regulator of mTORC1. ERK1/2 and the RSKs also collaborate in the regulation of ribosome biogenesis, by promoting TIF-1A phosphorylation. T-bars represent inhibitory signals, whereas arrows indicate stimulatory signals.



and MMP9), which play roles in the inflammatory response and tumor progression, respectively [198]. More recently, eIF4E phosphorylation stimulated by transforming growth factor-β (TGFβ) was found to be important for the translation of Snail and Mmp-3 mRNAs, which are involved in the induction of epithelial-to-mesenchymal transition (EMT) [212]. Therefore, the phosphorylation of eIF4E by the MNKs appears to play key roles in tumorigenesis and the metastatic process, suggesting that pharmacological inhibitors of MNKs represent a novel class of potential anti-cancer agents [209]. 7.2. The p90 ribosomal S6 kinases (RSKs) The RSK family is composed of four Ser/Thr kinases (RSK1, RSK2, RSK3 and RSK4) that are directly activated by ERK1/2 in response to diverse stimuli (Fig. 4) [186]. RSK family members exist in all vertebrate species and not so distant RSK orthologues have been identified in Drosophila and Caenorhabditis elegans. A notable feature of the RSK subfamily of MAPKAPKs is that they contain two distinct and functional kinase domains within the same polypeptide [213,214]. While the Cterminal kinase domain regulates RSK autophosphorylation and activity, the N-terminal kinase domain is thought to regulate the phosphorylation of all known exogenous substrates of RSK [183]. The N-terminal kinase domain belongs to the AGC family of protein kinases, explaining why several bona fide RSK substrates are also regulated by Akt and/or S6Ks [186]. All RSK isoforms are expressed at relatively high levels during development and adulthood, with the exception of RSK4, which is more abundant during embryogenesis [186,215]. RSK was originally identified as an in vitro rpS6 kinase [216,217], which suggested that RSK may be involved in translational control. Using rapamycin to inhibit mTORC1 demonstrated that the S6Ks were the predominant rpS6 kinases operating in somatic cells [218]. Subsequent studies using S6K1−/−S6K2−/− cells confirmed these findings, but also showed low-level residual rpS6 phosphorylation likely due to regulation by the RSKs [139]. In accordance with this observation, RSK was shown to specifically phosphorylate rpS6 on Ser235 and Ser236, in response to agonists of the Ras/MAPK pathway [219]. These findings indicated that rpS6 phosphorylation at these sites can occur in an mTOR-independent manner. The exact role of site-specific rpS6 phosphorylation remains elusive, but growing evidence suggests that rpS6 phosphorylation may be involved in fine-tuning the response to growth factors [151]. Interestingly, both ERK1/2 and RSK were shown to participate in rRNA synthesis by phosphorylating the residues important for the function of TIF-1A [220]. These findings suggest that the Ras/MAPK pathway collaborates with mTORC1 to regulate Pol I activity in response to growth factors. As indicated above, the Ras/MAPK pathway impinges on the PI3K/mTOR pathway at various steps to regulate mRNA translation (Fig. 4). In addition to its role upstream of mTORC1, RSK was shown to phosphorylate eIF4B at Ser422 both in vitro and in vivo [161]. Phosphorylation of eIF4B at this site was previously shown to promote capdependent translation [160], likely due to its ability to stimulate eIF4A RNA helicase activity [23]. eIF4G bridges the mRNA with the ribosome through its interaction with eIF3 [221], which was demonstrated to interact directly with eIF4B [222]. RSK-mediated phosphorylation of eIF4B was found to promote its interaction with eIF3 [161], suggesting a regulatory mechanism by which eIF4B is recruited to the translation initiation complex [161,165]. RSK may also regulate mRNA translation through the phosphorylation of GSK3β on Ser9, an inhibitory site [223,224]. Upon insulin treatment, GSK3β becomes inactivated, and this results in the dephosphorylation of eIF2B at an inhibitory site [225]. While eIF2B dephosphorylation likely contributes to translation initiation, it was shown to be insufficient for the activation of eIF2B by insulin [226]. Interestingly, activated GSK3β and AMPK were both shown to phosphorylate and activate TSC2 [118,227], suggesting that the Ras/MAPK pathway may inhibit TSC2 activity using both direct and indirect mechanisms. RSK

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was also shown to phosphorylate the eEF2 kinase [172], thereby regulating the elongation phase of translation. 8. Perspectives The regulation of mRNA translation plays a central part in the complex mechanism of cancer initiation and progression. In many cases, alterations in translational control drive the metabolic changes associated with tumorigenesis and metastasis. Many components of the translational machinery functionally interact with oncogenes and tumor suppressors that are part of signaling cascades underlying many human malignancies, such as the PI3K/mTOR and Ras/MAPK pathways. Components of the translational apparatus thus make attractive therapeutic targets, as they are found at the point of convergence of several oncogenic pathways. Translation inhibitors would therefore represent effective targeted therapies as tumors become increasingly dependent on enhanced protein synthesis. This is exemplified by the many translation initiation factors that are overexpressed across different cancers (Fig. 1) and the pathways regulating them (Fig. 3), demonstrating the addiction of cancer cells to having enhanced protein synthesis. The generally accepted role of translational control in the pathophysiology of cancer results from decades of work from researchers engaged in basic biomedical science using cultured cells and animal models. Together with translational approaches, these advances may enable the identification of novel drug targets that can be exploited to treat cancer, as well as other diseases linked to aberrant protein synthesis. The complete understanding of the genetic and biochemical mechanisms associated with drug targets will be required to maximize the likelihood of success in the clinic of potential translation inhibitors. Future studies need to more carefully investigate the molecular mechanisms governing mRNA translation, as we know very little about the regulatory events required for the specific translation of tumorpromoting mRNAs. Changes in the translation machinery that occur specifically in certain types of cancers should also be investigated, especially as they sometimes relate to the stage and grade of the disease, or resistance to chemotherapy. In conclusion, translational control is a relatively new area of cancer therapy, and the future will likely provide many opportunities for the development of translation inhibitors with anti-tumor activities. Acknowledgements The authors thank Neethi Nandagopal and members of the Roux laboratory for comments on the manuscript. Work in the P.P.R. laboratory is supported by grants from the Canadian Institutes of Health Research (MOP123408), the Cancer Research Society (DF127090), the Human Frontier Science Program, as well as the National Sciences and Engineering Research Council of Canada. P.P.R. is the Canada Research Chair in Cell Signaling and Proteomics. The Institute for Research in Immunology and Cancer core facilities are supported in part by Fonds de Recherche du Québec - Santé. References [1] F. Buttgereit, M.D. Brand, A hierarchy of ATP-consuming processes in mammalian cells, Biochem. J. 312 (Pt. 1) (1995) 163–167. [2] N. Sonenberg, A.G. Hinnebusch, Regulation of translation initiation in eukaryotes: mechanisms and biological targets, Cell 136 (2009) 731–745. [3] A. Ghazalpour, B. Bennett, V.A. Petyuk, L. Orozco, R. Hagopian, I.N. Mungrue, C.R. Farber, J. Sinsheimer, H.M. Kang, N. Furlotte, C.C. Park, P.Z. Wen, H. Brewer, K. Weitz, D.G. Camp II, C. Pan, R. Yordanova, I. Neuhaus, C. Tilford, N. Siemers, P. Gargalovic, E. Eskin, T. Kirchgessner, D.J. Smith, R.D. Smith, A.J. Lusis, Comparative analysis of proteome and transcriptome variation in mouse, PLoS Genet. 7 (2011) e1001393. [4] C. Vogel, S. Abreu Rde, D. Ko, S.Y. Le, B.A. Shapiro, S.C. Burns, D. Sandhu, D.R. Boutz, E.M. Marcotte, L.O. Penalva, Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line, Mol. Syst. Biol. 6 (2010) 400. [5] P.P. Roux, I. Topisirovic, Regulation of mRNA translation by signaling pathways, Cold Spring Harb. Perspect. Biol. 4 (2012).


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Crosstalk of Oncogenic Signaling Pathways during Epithelial-Mesenchymal Transition.

USP22 regulates oncogenic signaling pathways to drive lethal cancer progression.

Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders.

Independent and core pathways in oncogenic KRAS signaling.

Optogenetic control of intracellular signaling pathways.

Oncogenic Signaling Adaptor Proteins.

Activation of diverse signalling pathways by oncogenic PIK3CA mutations.

Narrowing the focus: a toolkit to systematically connect oncogenic signaling pathways with cancer phenotypes.

Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation.

MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways.

Oncogenic epigenetic control.

Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.

Regulation of oncogenic PI3-kinase signaling by JARID1B.

Immunotherapy and Oncogenic Pathways: The PTEN Connection.

Control of hepatitis B virus replication by interferons and Toll-like receptor signaling pathways.

Modulation of neurotrophic signaling pathways by polyphenols.

Predicting resistance by selection of signaling pathways.

Human Oncogenic Herpesvirus and Post-translational Modifications - Phosphorylation and SUMOylation.

Dynamic pathways of -1 translational frameshifting.

Hedgehog Cholesterolysis: Specialized Gatekeeper to Oncogenic Signaling.

Light-regulated translational control of circadian behavior by eIF4E phosphorylation.

Translational control of globin synthesis by low molecular weight RNA.

Translational control of mRNAs by 3'-Untranslated region binding proteins.

Control of the translational machinery by amino acids.