Ribosome biogenesis and global protein synthesis are tightly and dynamically regulated to accommodate the growth demands of a cell. Indeed, an increase in cell mass is a pre-requisite for accurate cell division. This is achieved by signaling pathways that simultaneously sense energy, stress, nutrient availability, as well as growth factors, and integrate these inputs to direct control of ribosome production and activity. One of the primary reasons for this cross talk is to integrate external stimuli such as energy and nutrient abundance, with the execution of cell growth and division that is directly coupled to protein synthesis. When these signaling pathways are altered, it may lead to unrestrained control of protein synthesis. Indeed, one of the earliest markers for cancer cells, discovered more than 100 years ago, is an increase in the size and number of nucleoli[20
]. This may reflect the increasing demands for ribosome biogenesis in cancer cells in order to sustain their elevated rates of growth and division. Is this a cause or consequence of cellular transformation? This question has been answered, at least in part, by the identification of several oncogenic signaling pathways that directly modulate the activity of specific translational components. Notable examples include the PI3K-Akt-mTOR and RAS-MAPK signal transduction pathways, as well as transcriptional programs regulated by oncogenic Myc [21
One of the best-studied examples of oncogenic signaling impinging on translational control is the PI3K-AKT pathway, which modulates translation initiation largely through activation of the kinase m
]. mTORC1 phosphorylates ribosomal protein S6 kinase 1/2 (S6K1/2) and the 4EBPs, which negatively regulate the major cap-binding protein eIF4E[27
]. The latter leads to a conformational change that releases 4EBPs from eIF4E and ultimately recruits the 40S ribosomal subunit to the 5’ end of mRNAs[29
]. Overexpression of eIF4E promotes cancer and cooperates with c-Myc to drive lymphomagenesis in vivo
in transgenic mice [31
]. 4EBPeIF4E exerts significant control over cap-dependent translation, cell growth, cancer initiation, and progression downstream of mTOR hyperactivation [33
]. Molecularly, eIF4E hyperactivation is able to enhance the translation of select mRNAs[35
]. The 5’UTR of these mRNAs are believed to harbor the regulatory elements that impart this selectivity, such as complex secondary structures. One example is Mcl-1, an anti-apoptotic factor containing a complex 5’UTR that is specifically translationally upregulated upon eIF4E hyperactivation leading to enhanced survival of cancer initiating cells [34
]. While mounting evidence, including elegant genetic studies, have clearly shown a central role of eIF4E hyperactivation in cancer development, the repertoire of translational target mRNAs that are specifically sensitive to eIF4E hyperactivation remains poorly defined. There are now emerging technologies that may facilitate their identification. In particular, the ability to deep sequence ribosome protected mRNAs will enable codon-by-codon resolution of ribosome occupancy on specific mRNAs [37
]. Furthermore, through deep sequencing, it is also now possible to determine the secondary structures of mRNAs by using a novel strategy termed parallel analysis of RNA structures (PARS) [38
]. The combination of these two technologies may provide a very accurate portrait of how mRNA secondary structures control cap-dependent translation and impact on translation of the cancer genome.
Regulation of eIF4E is not the only node where information from signaling pathways is received by the translational machinery. It is now also clear that an entire repertoire of translational components may be co-opted to promote cancer initiation. For example, AKT hyperactivation also modulates translation elongation [39
] (). Additional regulated translational components include eIF2α, which is part of the ternary complex required to chaperone the initiator tRNA to the ribosome. eIF2α is commonly overexpressed in cancers and may thereby provide an uncontrolled stimulus leading to increased rates of protein synthesis [40
]. Interestingly, even overexpression of the initiator tRNA itself is able to drive cellular transformation [41
]. Another translation factor that promotes cellular transformation is eIF6. eIF6 regulates the joining of the 60S ribosomal subunit to the 48S pre-initiation complex to initiate translation [42
]. Importantly, eIF6 has been shown to be rate limiting for translation, cell growth and transformation[42
]. Interestingly, eIF6 interacts with RACK1, a ribosome associated scaffolding protein that coordinates signaling by PKC and src kinases [43
]. Therefore, signaling through RACK1 to eIF6 may be another important node of oncogenic regulation.
A prominent example of an oncogenic signal that relies on the translational machinery for cellular transformation is the Myc oncogene, which is commonly deregulated in human cancers[44
]. Myc directly increases protein synthesis rates by controlling the expression of multiple components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, Pol III and rDNA[24
]. Genetic strategies that restore increased protein synthesis in Myc transgenic mice to normal levels reveal that the oncogenic potential of Myc is suppressed in this context [47
]. These findings also demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression[47
]. Surprisingly, deregulations in mitotic translational control as a consequence of Myc hyperactivation also directly lead to genome instability by modulating the translation of specific mRNAs[47
]. Thereby, Myc-dependent control of the translational machinery has a pleiotropic role in distinct steps of cancer initiation and progression.
The remarkable repertoire of translational components found deregulated in cancer, whose activity is directly controlled downstream of specific oncogenic signals, strongly supports a critical and causal role in cancer initiation and progression. What is also emerging from these studies is that perturbations in translational control provide a highly specific outcome for gene expression, genome instability, and distinct steps along the pathway towards cancer development.