Review

Oncogene (2004) 23, 3248–3264. doi:10.1038/sj.onc.1207546

Postgenomic global analysis of translational control induced by oncogenic signaling

Vinagolu K Rajasekhar1,2 and Eric C Holland1

  1. 1Department of Surgery (Neurosurgery), Neurology, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
  2. 2Department of Molecular Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA

Correspondence: VK Rajasekhar, E-mail: vinagolr@mskcc.org (VKR); EC Holland, E-mail: hollande@mskcc.org (ECH)

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Abstract

It is commonly assumed that developmental and oncogenic signaling achieve their phenotypic effects primarily by directly regulating the transcriptional profile of cells. However, there is growing evidence that the direct effect on transcription may be overshadowed by differential effects on the translational efficiency of specific existing mRNA species. Global analysis of this effect using microarrays indicates that this mechanism of controlling protein production provides a highly specific, robust, and rapid response to oncogenic and developmental stimuli. The mRNAs so affected encode proteins involved in cell–cell interaction, signal transduction, and growth control. Furthermore, a large number of transcription factors capable of secondarily rearranging the transcriptional profile of the cell are controlled at this level as well. To what degree this translational control is either necessary or sufficient for tumor formation or maintenance remains to be determined.

Keywords:

AKT, cancer, eiF-4E, oncogenic signal, Ras, translation

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Introduction

In many ways, oncogenesis may be thought of as an abberency of development (Vogelstein and Kinzler, 1993; Loeb et al., 2003). The mechanisms that drive oncogenesis can be traced to an altered expression pattern of genes related to growth and development (Hahn and Weinberg, 2002); the ultimate effect of gene expression is protein production, and that requires mRNAs to be recruited to ribosomes. During early embryogenesis, rapid shifts in protein production are required as cells divide and differentiate in response to intercellular communication. Such control may require more rapid responses than can be achieved simply by differential transcription and changes in steady-state total mRNA levels (Sager, 1997). Differential recruitment of existing mRNAs to polysomes could contribute to the rapid responses required in this and other signal transduction related processes (Rao et al., 1983). Thus, the parallels between development and oncogenesis also raise the possibility that some of the abnormalities in a cancer cells's proteome may be achieved by differential recruitment of mRNAs to polysomes (Dua et al., 2001). The mRNAs that would affect the process of embryonic development and oncogenesis encode proteins involved in cell-to-cell signaling, cell cycle control, and apoptosis (Herbert et al., 2000; Polunovsky et al., 2000; Calkhoven et al., 2002). This possibility is supported by the poor correlation observed between protein and RNA in eucaryotic systems, where up to 20-fold changes in protein levels can be seen without corresponding alterations in mRNA abundance, and up to 30-fold changes in mRNA levels without reflection on protein levels (Kleijn et al., 1998; Gygi et al., 1999).

While the importance of translational control in cell cycle, and the role of cell cycle-dependent activation of translational initiation in transformation are known (Lazaris-Karatzas et al., 1990; Rhoads et al., 1993; Flynn and Proud, 1996; Sonenberg and Gingras, 1998; Zimmer et al., 2000), interest in the regulatory mechanisms of translational control in tumorigenesis is just being appreciated (Kleijn et al., 1998; Willis, 1999; Meric and Hunt, 2002; Watkins and Norbury, 2002; Graff and Zimmer, 2003; Ruggero and Pandolfi, 2003). Initiation of translation is the primary step that determines the rate of protein synthesis. Considerable progress has been made in our understanding on the mechanism of translational initiation and on how modulation of general translational machinery regulates gene-specific protein synthesis (Dever, 2002). Thus, identifying the signal transduction pathways involved in translational control of specific mRNA species during tumorigenesis is critical (Brown and Schreiber, 1996; Waskiewicz et al., 1997; Proud et al., 2001; Martin, 2003; Shamji et al., 2003; Sonenberg and Dever, 2003; Gingras et al., 2004). To this end, this review will present a brief overview of the translational regulatory process, emerging signaling pathways that appear to modulate translation, and finally the prospects of global analysis of translational control during induced oncogenesis.

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Translation and translational regulation in cancer

The expression of many eucaryotic genes, including some that are regulated at the transcriptional level are also regulated at the level of translation. There are several ways that the translational efficiency of a given mRNA can be modulated, such as changes in the levels and activity of protein synthesis machinery, mutations affecting the structure of the mRNA, or altered signal transduction pathways. Unlike the prominent role of base pairing between rRNA and 'Shine Delgarno sequence preceding the initiation codon of each open reading frame (ORF) in procaryotes, the first step in eucaryotic translation, the ribosome binding to mRNA in a process referred to 'initiation of translation', is much more complex, involving a finely tuned network of initiation factors (Pestova et al., 2001). In addition to initiation, elongation of the peptide chain and termination represent the essential steps of the translation process. Various specific initiation factors, elongation factors, and termination factors participate to execute successfully the process of protein synthesis.

An overview of translation

Virtually all cellular mRNAs are cotranscriptionally capped at their 5' termini with a characteristic 7-methyl G(5') pppX (where X is any nucleotide) structure and many of them contain poly(A) chain at the 3'end. A detailed account of various effectors mediating mRNA recruitment to ribosomes has been described (Gingras et al., 1999a). Binding of eucaryotic initiation factor (eiF)-4E to the cap structure in the mRNA is the earliest event in the initiation of translation and also appears to be the rate-limiting step in the translation per se. Then, the eiF-4E delivers cellular mRNAs to a heterotrimeric eiF-4F complex to facilitate the 43S ribosome recruitment. Thus, in addition to eiF-4E, the eiF-4F complex is composed of eiF-4A (the ATP-dependent RNA helicase facilitating secondary structure melting) and eiF-G (the scaffolding protein that binds eiF-4E and eiF-4A). Association of eiF-G with eiF-4E appears to increase the affinity between eiF-4E and the cap by at least 10-fold. Furthermore, the eiF-G interacts with poly(A) binding protein (PABP), which binds the 3' end poly(A) tail of the mRNA, the eiF-4E phosphorylating kinase MNK1, and the eiF3 multiprotein complex. Of interest, PABP also interacts with other PABP binding proteins (Paips), eiF-4B, which also directly interacts with eiF-4F and aids in the processitivity of eiF-4A, and eucaryotic releasing factor (eRF) 3. These functional interactions at the two termini lead to the circularization of the mRNA, a functional prerequisite for efficient translation initiation (Sachs and Varani, 2000). The eiF-4F complex then scans from 5' cap down stream towards AUG start codon, by transiently melting secondary structures near the 5' end with the help of additional RNA binding proteins eiF-4B and eiF-4 H. This unwinding enables eiF3 to access the below described preinitiation complex. The eiF2-GTP mediates the binding of the initiating methionyl-tRNA (Met-tRNAf) onto the smaller (40S) subunit of the ribosome by forming a ternary complex and this process is enhanced by additional factors, eiF3 and eiF1A, that contribute to the formation of 43S preinitiation complex. Binding to the eiF-G results in formation of a stable 48S complex. On most mRNAs, translation is initiated at the AUG codon closest to the 5'end and is dependent on base pairing with the anticodon of the Met-tRNAf and other initiation factors such as eiF1, eiF2, eiF5, and eiFA, along with the hydrolysis of GTP (Sachs and Varani, 2000; Dever, 2002). The initiation factors are then released and eiF2-GDP is recycled by guanine nucleotide exchange factor eiF2B to eIF2-GTP. This step is then followed by an eiF5B mediated GTP hydrolysis-dependent large (60S) ribosomal subunit joining. The resulting 80S ribosome (upon the release of eiF5B), is now poised to accept the first elongating aminoaceyl-tRNA by GTP-dependent activity of eucaryotic elongation factor (eEF) 1. Following the peptide bond formation, translocation of the ribosome relative to the mRNA is catalysed by another GTP-dependent activity of eEF2 bringing the next codon into position. As the termination codon is reached in this journey towards the 3' end on the mRNA, the peptide chain releasing factors eRF1 and eRF3 bring about the hydrolysis of the last peptidyl-tRNA bond and release the polypeptide. At the same time, by an unknown regulatory mechanism, the eiF3 dissociates the ribosome into its subunit particles, which become available for another round of translation.

Role of eiF-4E

Nearly 80–85% of the eiF-4E present in 48S initiation complex is phosphorylated, in contrast to 50% phosphorylation of the uncomplexed eiF-4E. Although eiF-4E phosphorylation increases the rate of protein synthesis up to four-fold in the majority of cases, dephosphorylation of eiF-4E also induces eiF-4F formation and protein synthesis in other cases, suggesting only enhancing but nonessential function of phosphorylation of eiF-4E (Kleijn et al., 1998; McKendrick et al., 2001). This contention gets support from the observations that only upon binding to eiF-4G does eiF-4E appear to get phosphorylated to enhance translation (Flynn and Proud, 1996; Pyronnet et al., 1999; Waskiewicz et al., 1997). An activity-dependent switch to cap-independent translation is also reported to be triggered by eiF-4E dephosphorylation (Dyer et al., 2003). It is interesting to note that there is a little or no role for phosphorylation of eiF-4E during cell differrentiation (Kleijn et al., 1998), while the phosphorylation is critical in cell growth (Lachance et al., 2002). Conversely, treatment with peptides based on conserved eiF-4E binding motifs in eiF-4G and 4E-BPs that specifically prevent engagement of eiF-4E with eiF-4G rapidly induced cell death (Herbert et al., 2000). Since substitutions in the peptides that disrupt binding to eiF-4E do not cause apoptosis, an additional direct role for eiF-4E in survival unlinked to its known role in translation is possible. It remains to be seen if the phosphorylated eiF-4E by some mechanism may confer specificity in enhancing the translation rates of malignancy-related mRNAs relative to others. Since a fraction of eiF-4E is also colocalized in the nucleus with splicing factors in speckles, eiF-4E has been suggested to involve additionally processing a specific subset of mRNAs in the nucleus and/or exporting them into the cytoplasm (Dostie et al., 2000). As nearly 50% of the human transcripts involve alternative splicing (Modrek and Lee, 2003), it is possible that enhanced accumulation of eiF-4E may have a causal link to the aberrant splicing of certain growth-promoting and oncogenic mRNAs, comparable to the splicing defects recorded in various forms of cancer (Xu and Lee, 2003). Overexpression of eiF-4E increases cyclin D1 production by stimulating its mRNA export (Rousseau et al., 1996). It is not known if eiF-4E stimulates the mRNA export directly through its association with the cap from the nucleus or indirectly by increasing the translation of specific mRNAs. In any case, the accumulation of eiF-4E readies certain mRNA for preferential translation instantly upon a trigger of signaling. The S6 ribosomal protein (S6RP) of the 40S ribosomal subunit is implicated in RNA binding and upon phosphorylation, and it is also suggested to enhance the translation of a subset of the mRNAs that contain 5' terminal oligopyrimidine tract (TOP) (Avni et al., 1997; Meyuhas, 2000). The TOP mRNAs encode translation elongation factors and many ribosomal proteins.

Critical protein–protein interactions in translation initiation

Two sets of protein interactions play vital roles in translation initiation: (1) the eiF-4E binding proteins (4E-BPs) compete with eiF-4G for binding to eiF-4E and inhibit the translation initiation. Hierarchical phosphorylation of 4E-BP prevents its binding to eiF-4E and thereby relieves its inhibitory effect on eiF-4E (Gingras et al., 1999b), and (2) eiF2B is a heterotrimeric guanine nucleotide exchange factor (GEF) for eiF2. In contrast to monomeric GEFs for Ras and related G proteins, eiF-2B is a heteromic complex of five subunits. Phosphorylation of eiF2alpha by eiF2alpha protein kinase, PKR converts eiF2 from a substrate to a competitive inhibitor of eiF2B. Consequently, formation of a complex between eiF2-GTP–Met.tRNA does not take place and global protein synthesis is inhibited. Translation inhibition of specific mRNAs such as GCN4, ATF4, and C/EBP occurs in addition to gene-specific control of translation by specialized mRNA binding proteins (Dever, 2002; Ostareck et al., 2001).

Translation and cancer

Overexpression of translation initiation factors like eiF-4E and eiF-4G, or dominant-negative PKR causes neoplastic cellular transformation in fibroblast and epithelial model cell systems (Lazaris-Karatzas et al., 1990; Clemens and Bommer, 1999; De Benedetti and Harris, 1999; Graff and Zimmer, 2003). The observed eiF-4E-induced transformation may result from increased translation of mRNAs encoding oncogenic proteins (Rosenwald et al., 1993, 1995; Rousseau et al., 1996; Shantz et al., 1996). Conversely, reducing the eiF-4E levels (DeFatta et al., 2000; Nathan et al., 2000), or overexpressing 4E-BP1, thereby preventing the availability of free eiF-4E to form the eiF-4F complex (Rousseau et al., 1996; Graff and Zimmer, 2003), suppresses tumorigenicity and angiogenesis. Dysregulation and overexpression of several translational initiation factors, elongation factors, and other mRNA binding proteins related to translation-enhancing function, such as YB-1 and ribosomal proteins, have also been observed in a large number of cancers and cancer types (Table 1), underscoring the significance of translational activation in tumor formation and invasion.


Cis-acting elements within an mRNA structure controlling translation and involvement of micro RNAs

Apart from the components of translational machinery, the efficiency of protein synthesis can also be regulated by various structural features of the mRNAs, particularly at the 5' and 3' termini (Wilkie et al., 2003). These include (1) long and structured 5'-untranslated regions (UTRs), (2) unusual or multiple upstream initiation codons, (3) upstream ORFs, (4) internal ribosome entry sites (IRES), and (5) 5'-TOP sequences. For example, the majority of the growth factor-encoding transcripts contain 100–150 base long sequences in 5'UTR that are up to 90% GC rich and have the potential to form extended stem loop structures, thereby requiring the need for the eiF-4E-dependent translation initiation (Clemens and Bommer, 1999). FGF2 and c-Myc mRNAs utilize additional and unusual initiation codons such as CUG to synthesize proteins depending on cellular conditions (Willis, 1999). The mRNAs of many oncogenes contain long and structured areas within the 5'UTR and feature a polypyrimidine tract towards the 3' end, which are utilized as IRES. Such transcripts employ cap-independent translation initiation in the absence of some or all initiation factors. Short and unstructured 5' UTRs about 40 nucleotides in length, which also bear up to 14 consecutive oligopyrimidine residues help, in growth-dependent translation of ribosomal proteins with a casual relationship to phosphorylation of S6RP (Meyuhas, 2000). Similarly, in quiescent cells, where eiF-4E activity is repressed and global translation declines, p27Kip1 translation is highest utilizing an IRES in the 5'UTR of the mRNA (Miskimins et al., 2001). Distinct adenosine uridine-rich elements (ARE) are found in the 3' UTR of many mRNAs encoding inflammatory cytokines and growth factors, which influence the stability of their own mRNAs in breast cancer (Balmer et al., 2001).

Other distinct sequences that regulate mRNA localization are found in the 3'UTR, which appear to function by interacting with transacting and noncoding small RNA, referred to as microRNA (miRNA) (Baehrecke, 2003; Lai, 2003). The miRNAs are endogenously encoded, produced by processing of small single-stranded hairpin precursor transcript, and shown to function as antisense regulators of gene expression (Ambros, 2003). Recognition and translational inhibition of the target mRNAs via imprecise antisense base pairing is one of the mechanisms of miRNA function (Wightman et al., 1993; Olsen and Ambros, 1999; Seggerson et al., 2002). Extensive regulation of miRNAs occurs during brain development. Several miRNAs are associated with polyribosomes in primary neurons, where they are likely to modulate translation (Krichevsky et al., 2003). The miRNAs also associate with distinct ribonucleoproteins affecting preferential translational initiation (O'Donnell and Warren, 2002). These data suggest a specificity factor role in translation analogous to the function of let-7 miRNA in repressing the translation via 3'UTR of hunchback in the Caenorhabditis elegans nervous system (Abrahante et al., 2003; Lin et al., 2003). Interestingly, even the short interfering RNA (siRNA) mediated translational repression, which also occur via partially complementary binding sites in the 3'UTR of mRNAs (Doench et al., 2003), additionally requires eiF2C translation initiation factors (Doi et al., 2003). While some of the miRNAs such as bantam are implicated in cell proliferation via translational repression due to interaction with the conserved 3'UTR of mRNAs (Brennecke et al., 2003), frequent deletions and down regulation of miRNA genes for miR15 and miR16 at 13q14 in human chronic lymphocytic leukemia suggest an additional tumor suppressor role for some of the miRNAs (Calin et al., 2002). Several transcripts with structural features affecting translation were reported to be associated with various oncogenic phenotypes (Table 2).


Trans-acting mRNA binding factors regulating translation

It is not possible to review comprehensively all that is known about 5' and 3' UTR binding proteins and how the cognate cis-acting regulatory sequence elements in the mRNAs react to affect the final protein production. However, identifying and understanding the regulation of functionally related and dynamic links between 5' and 3' UTRs is the functional theme in the context of current cancer biology. For example, recent identification of translational repression via a cytoplasmic polyadenylation element (CPE) within the 3'UTR of some messages like that of cyclin B1 opened up novel regulatory pathways for selective translational control influencing the eiF-4E-dependent translation initiation (Groisman et al., 2002; Wilkie et al., 2003). A protein that binds to CPE (CPEB), depending on its phosphorylation status, performs a dual control in translation, either activation or repression. The CPEB-mediated repression is accomplished while in its dephosphorylated state by an interaction with TACC family proteins and its subsequent interaction with eiF-4E. The TACC protein with sequence similarity to eiF-4G and 4E-BP binds to eiF-4E and thus prevents the formation of eiF-4F complex. By contrast, in its phosphorylated state CPEB interacts with a cleavage and polyadenylation specificity factor (CPSF) that recognizes the CPE downstream hexanucleotide element AAUAAA. The CPSF in turn interacts with poly (A) polymerase (PAP) catalysing the poly(A) addition. A protein that binds to the newly elongating poly(A) chain (PABP) also interacts with eiF-4G resulting in a complex that effectively displaces TACC from eiF-4E allowing the eiF-4F complex formation. As the cells begin to exit the M-phase of the cell cycle, a phosphatase inactivates CPEB, leading to deadenylation and loss of PABP as well as a reassociation of TACC with eiF-4E, and thereby translational silencing as has been demonstrated for translation control of cyclin B1 mRNA. Apart from the dynamic regulatory control of CPEB, its interacting partner TACC1 is downregulated in several human cancers (Conte et al., 2002), which may represent additional mechanisms for escaping translational repression and preventing mitotic exit. Alternative pathways to the above-described cap-dependent translation initiation also exist and utilize an IRES in the mRNAs in the absence of some or all initiation factors.

Specific mRNAs that encode proteins involved in both development and cancer are regulated in part at the translational level

It would not be surprising if the production of critical proteins was regulated at many levels in order to maintain tight control over the rapid changes that occur during early embryogenensis. There are many examples of mRNAs encoding proteins involved in signal transduction and cell cycle control that are regulated at many levels, including translation. For example, the insulin-like growth factor (IGF) ligand signals through the IGF-II receptor and is mediated by a family of binding proteins known as the IGF binding proteins (IGFBPs) (el-Badry et al., 1991; Nielsen et al., 1995). Recruitment of the mRNAs for IGFBP 4 and IGFBP5 to ribosomes has been shown to be strongly dependent on oncogenic signaling through the Ras and Akt pathways (Rajasekhar et al, 2003). Aberrant Notch signaling is associated with the development of human cancers (Allenspach et al., 2002; Nickoloff et al., 2003). Dysregulated expression of a series of tumor-specific 5'-deleted Notch1 mRNA transcripts in a subset of lymphoid neoplasms (Aster and Pear, 2001) as well as lack of correlation between the levels of Notch mRNAs and proteins in different layers of basal cell carcinoma (Lowell et al., 2000; Nickoloff et al., 2002) suggest that some of the control over Notch protein production rests at the level of translation. Furthermore, neoplastic transformation by Notch is independent of transcriptional activation (Dumont et al., 2000), suggesting involvement of post-transcriptional and translational elements in this process. While levels of the mRNA encoding the cyclin-dependent kinase inhibitor p27Kip1 remain constant during cell cycle exit and maintenance in the quiescent state, p27 protein accumulates to large amounts by a modulation of translational efficiency (Agrawal et al., 1996; Hengst and Reed, 1996). These are but a few examples of this effect; a more complete list can be found in Table 2. In addition to translational control, expression of these genes is frequently regulated at other levels as well.

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Signaling pathways that affect translational control in oncogenesis

Signaling pathways that regulate development are not only frequently dysregulated in neoplastic proliferation but also causally related to cancer formation in experimental systems. However, it is not clear how the specificity and complexity of cellular response to a particular signaling pathway is achieved during oncogenesis. The growing number of indentified signaling components continue to complicate the attempts to dissect the cancer-specific molecular signaling pathways. Although there are likely to be translational effects of many if not all of the signaling pathways involved in embryogenesis and oncogenesis, the ones best documented to date are the tyrosine and seriene kinase receptors, and cytoplasmic protein tyrosine kinases.

Receptor serine kinase signaling

Members of transforming the growth factor beta (TGF-beta) superfamily represent transmembrane receptors that are activated as serine kinases by docking with cognate ligands such as TGF-beta and bone morphogenetic proteins (BMPs). There receptors signal through intracellular transducers called Smads (R-smads). Most cancers retain TGF-beta receptors, but attenuate TGF-beta-mediated antimitogenic effects through autocrine and paracrine signaling. Translational initiation on a number of growth receptor mRNAs, including that of TGF-beta, is specifically regulated during growth, differentiation, and stress (van der Velden and Thomas, 1999; van der Velden et al., 2000).

Apart from substantial focus on transcriptional events, involvement of post-transcriptional effects also plays a role in TGF-beta-mediated oncogenesis as illustrated below. The eiF2 alpha subunit is associated with kinase inactive TGF-beta II R (McGonigle et al., 2002). Insulin via insulin growth factor receptor (IGFR) regulates the 5'UTR of TGF-beta 1 to induce translationally synthesis of TGF-beta 1 without affecting its mRNA stability, at least during renal interstitial fibrosis (Morrisey et al., 2001), indicating that controls beyond transcription may participate in regulating the TGF-beta pathway. The normal mRNA for TGF-beta 3 contains a long 5'UTR that exerts a potent inhibitory effect on its translational efficiency and is deleted in a transcript with a considerably foreshortened 5'UTR found in human breast cancer cells. This latter transcript is more actively engaged in translation on polysomes (Arrick et al., 1991). TGF-beta also promotes attachment and spreading of malignant astrocytoma cells by increasing paxillin protein production through an enhancement in translation unassociated with changes in steady-state levels of paxillin mRNA (Han et al., 2001). Ectopic expression of eiF-4E in human colon cancer cells promotes the TGF-beta stimulation of adhesion molecules (Rajagopal and Chakrabarty, 2001). Collagen mRNA translation is also enhanced by TGF-beta in an anaplastic thyroid carcinoma model system (Dahlman et al., 2002). TGF-beta stimulates multiple protein interactions with a unique cis element in the 3'UTR of the mRNA encoding the receptor for hyaluronan-mediated motility (RHAMM), whose expression is elevated in transformed cells (Amara et al., 1996). Additionally, TGF-beta signaling acts on the 5'UTR of cyclin-dependent kinase 4 (cdk4) to block the progression through G1 (Miller et al., 2000).

Cytoplasmic protein tyrosine kinase (CPTK) signaling

c-Abl is one of nearly 32 known nonreceptor CPTKs, several of which have been implicated in human cancers (Blume-Jensen and Hunter, 2001). c-Abl directly binds to the mammalian target of rapamycin (mTOR) and inhibits its autophosphorylation, resulting in the inhibition of p70S6 kinase (Kumar et al., 2000). The c-Abl protein consists of SH(Src-homology)3, SH2, PTK, DNA binding, and actin binding domains, among others. While the c-Abl associates with ataxia–telangiectasia mutated (ATM), which may contribute to the activation of c-Abl in response to DNA damage and inhibition of 5' cap-dependent translation, ATM also independently phosphorylates 4E-BP1 (Yang and Kastan, 2000) with the significance to be understood. The transforming effects of other CPTKs, Bcr/Abl and Janus PTKs (JAKs), are also mediated by Ras/Raf/Erk pathway and PI3 kinase pathways (Blume-Jensen and Hunter, 2001; Verma et al., 2003). In particular, Bcr/abl increases the translation of mdm2 mRNA by facilitating the interaction of La antigen (in tyrosine kinase-dependent manner) with the 5'UTR of the mRNA (Trotta et al., 2003). Upregulation of eiF-4E and eiF-2alpha was found in v-Src- and v-Abl-transformed cells (Rosenwald, 1996). These data suggest that the translational controls may be integral components of the effects achieved by CPTK signaling.

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Signaling networks, crosstalk, and scaffolds involving Ras and Akt pathways during translational control in oncogenesis

Owing to cell–matrix and cell–cell interactions, cells perceive signals through many different growth factor receptors. They integrate signal information appropriately into various transcription, translation, and post-transcriptional/translational processes to regulate eventually diverse vital steps in cell growth, differentiation, and proliferation. Depending on developmental status and cellular context, different cell types generate different outcomes through a complex network (Guerra et al., 2003; Ptashne and Gann, 2003).

There are many prototypic growth factor tyrosine kinase receptors that are involved in oncogenic signaling, including EGFR, platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), hepatocyte growth factor receptor (HGFR), and IGFR, (Blume-Jensen and Hunter, 2001). Signaling by RPTKs involves cognate ligand-induced receptor dimerization or oligomerization, tyrosine autophosphorylation of the receptor subunits mediating specific binding of cytoplasmic signaling proteins containing (SH2) and protein tyrosine kinase binding domains such as growth factor receptor binding protein (Grb), RasGAP, and lipid kinase phosphoinositide 3-OH kinase (PI3 kinase) and activate various downstream signaling events.

Ras/Raf/Erk pathway

The Ras gene family represents some of the most frequently mutated oncogenes in various human tumors. While K-ras oncogenes are found in almost 90% of pancreatic cancers, and 50% of colon cancers, and 25% of adenomas, nonmutated but pathologically elevated Ras activity is found in other tumors such as glioblastoma. Activated Ras interacts with more than 20 effectors, including Raf-1 serine/threonine kinase, PI3 kinase, and Ral GDS, which are found to participate in various cancers.

Raf proteins are directly activated by Ras and relay signal information to MAPK/Erk kinase (Mek) and then to Erk. Mutations in Raf-1 genes were found in 70% of human malignant melanomas (Mercer and Pritchard, 2003). Activated Erk phosphorylates various factors involved in transcription and translation, tissue invasion, and metastasis, apoptosis evasion, and proliferation. For example, Erk activates several transcription factors, including the Ets family members and myc, and consequently increases transcription of multiple genes, some of them encoding RPTKs such as EphA2. These in turn down regulate wild-type (but not oncogenic) Ras via p120RasGAP (Miao et al., 1996), and cMyc target genes such as eiF-4E. Erk also phosphorylates eiF-4E via Mnk to enhance initiation of translation and/or via translational control of the antiapoptotic function (Polunovsky et al., 2000) of caspase 9 to inhibit its proteolytic cleavage (Allan et al., 2003). More interestingly, Ras/Raf-1/Erk pathway is organized by a variety of scaffolding proteins to insulate a specific portion of the pathway. For example, Raf kinase inhibitor protein (RKIP) negatively regulates the pathway by blocking the interaction between Raf-1 with Mek and is inactivated upon phosphorylation by activated Erk. This positive feedback loop occurs in breast and prostrate cancers, where RKIP expression was found to be downregulated (Martin, 2003). This effect is accomplished by suppression of Ras-stimulated transformation via c-jun NH2-terminal kinase (JNK) signal transduction pathway (Kennedy et al., 2003), or Raf-1-independent deregulation of p38 MAPK cascade (Pruitt et al., 2002). Activation of eiF2B and phosphorylation of 4E-BPs as well as eiF-4G by insulin treatment (Proud and Denton, 1997; von Manteuffel et al., 1997; Kleijn et al., 1998), phosphorylation of eiF-4B and eiF-4G via EGF-mediated stimulation of S6 Kinase (Wolthuis et al., 1993; Kleijn et al., 1998), and phosphorylation of 4E-BP1 and increase in protein synthesis (Wang and Proud, 2002) are mechanisms of Ras-mediated translational control in oncogenesis.

PI3 kinase/Akt pathway

This pathway represents an important node transducing the information of the multiple cellular signaling pathways initiated by PI3 kinase (Vivanco and Sawyers, 2002; Luo et al., 2003). The PI3 kinase is not only activated by growth factor-dependent RPTK (class 1A subgroup) and G-protein-coupled receptors (class 1B subgroup) but also by direct interaction with oncogenic Ras. PI3 kinase is a heterodimeric enzyme consisting of a regulatory p85 subunit and a catalytic p110 subunit. The p85 is encoded by three genes, alpha, beta, and italic gamma, and regulated by alternative transcript splicing. The gene is mutated in ovarian and digestive tract tumors. The p110 catalytic subunit is also encoded by three genes, alpha, beta, and italic gamma and this gene is amplified in human ovarian cancers. Upon activation, PI3 kinase phosphorylates phosphoinosides (PI), a process reversed through the dephosphorylation of 3' PI by the tumor suppressor phosphatase (PTEN). The gene encoding PTEN is mutated or silenced in a wide range of human tumor types. PI3 kinase also exists in three classes with multiple subunit isoforms. So far, only the class IA subgroup has been shown to be involved in oncogensis. The 3' PI-dependent serine/threonine kinase, PDK1, and Akt (cellular homolog of retroviral v-Akt) sequentially initiate a kinase cascade that plays a central role in growth regulation. Of the three ubiquitously expressing Akt isoforms, Akt1 is the dominant form in all tissues, Akt2 is expressed in insulin-responsive tissues such as skeletal muscle, heart, liver and kidney and Akt3 is higher in the testis and brain. Although dimer- or tri- or even multimerization of Akt is required for Akt activity, it is not known if the homo or hetero-merizations of Akt plays any role in oncogenesis. Akt activity is indirectly inhibited by PTEN, activated by the Src family tyrosine kinase Lyn and a carboxy terminal modular protein (CTMP). The chaperone heat-shock protein (HSP90) protects Akt from dephosphorylation by PP2A. Deregulated Akt is oncogenic; the gene is amplified in ovarian, pancreatic, and breast tumors and the activity is constitutively increased in brain and thyroid tumors (Choe et al., 2003). Akt phosphorylates several downstream targets and achieves many biological effects related to survival, proliferation, and cell growth. For example, Akt-mediated phosphorylation-dependent inactivation of proapoptotic BAD and caspase-9, or inhibition of nuclear localization of forkhead transcription factor (FKHP), will facilitate survival. In addition, Akt also phosphorylates GSK3beta and thereby prevents it from phosphorylating and targeting cyclin D1 for degradation or WAF1 (CIP1) from binding to proliferating cell nuclear antigen (PCNA).

The growth control function of Akt is largely accomplished by regulating translation via activation of its downstream kinase mammalian target of rapamycin (mTOR)-dependent mTOR/S6K/4E-BP1 signal transduction pathway. The activation of mTOR by Akt appears indirect and may involve a tumor suppressor complex composed of hamartin (TSC1) and tuberin (TSC2) heterodimer proteins associated with an autosomal dominant genetic disorder, tuberous sclerosis (TSC). The TSC1/2 acts to constrain mitogen-induced mTOR downstream signaling pathway (Tee et al., 2003) and leading to inhibition of protein translation. Phosphorylation of the TSC2 by Akt disrupts TSC2 binding to TSC1 and relieves this repression (Manning and Cantley, 2003). In the absence of Akt-mediated phosphorylation, TSC2 in the heterodimer complex, through its C-terminal GAP domain, directly functions as a GTPase activating protein (GAP) of a small G protein, Rheb (Ras homologue enriched in brain) (Garami et al., 2003; Inoki et al., 2003; Stocker et al., 2003). Activated Rheb (Rheb-GTP) requires membrane localization by farnesylation to activate specifically the mTOR/S6K/4E-BP1 pathway (Tee et al., 2002). Rheb-GTP was shown to transform NIH3T3 cells as wild-type Raf1 or H-ras (Yee and Worley, 1997). Impaired Rheb function is sufficient to suppress the phenotypic consequences of PTEN or TSC1/2 loss (Stocker et al., 2003).

Activated mTOR regulates translation through hierarchical phosphorylation either by activation of p70S6 Kinase (S6K1 and S6K2), implicated in the increased translation of 5'TOP mRNAs, and/or by inactivation of 4E-BP1 that inhibits cap-dependent translational initiation. Recently, a regulatory associated protein of mTOR, raptor (Hara et al., 2002; Kim et al., 2002), has been identified as an mTOR scaffold protein. Raptor also associates with p70S6 kinase and 4E-BP1 through their respective C-terminal conserved TOR signaling (TOS) motifs (Choi et al., 2003; Nojima et al., 2003; Schalm et al., 2003). More recently, a new protein named GbetaL has been identified as an additional component of the mTOR signaling complex. GbetaL binds to the kinase domain of mTOR independent of raptor and stimulates the kinase activity of raptor towards itself or towards p70S6 kinase and 4E-BP1 (Kim et al., 2003). GbetaL also stabilizes the interaction between raptor and mTOR, while facilitating a nutrient sensitive raptor-mTOR/GbetaL complex formation that decreases mTOR kinase activity during nutrient-limiting conditions (Kim et al., 2003). This provides a mechanism by which cellular responses regulate mTOR signaling to modulate the translational control. Without affecting the 4E-BP1 phosphorylation status, Akt also induces transformation by reducing synthesis of YB-1, a protein that binds mRNA as well as inhibits both cap-dependent and IRES-dependent translation (Aoki et al., 2001; Martin de la Vega et al., 2001). For example, growth factor induction of cyclin D expression is controlled at the translational level by PI3 kinase/Akt/mTOR pathway (Muise-Helmericks et al., 1998). PI3 kinase-dependent but Akt-independent pathways (such as the activation of small GTP binding proteins CDC42/Rac1, protein kinase C, and the serum and glucocorticoid-inducible kinase (SGK), or PI3 kinase-independent phosphorylation of Akt (e.g. via elevated cyclic AMP-mediated protein kinase A) also enhance translation (Blume-Jensen and Hunter, 2001). Their effect on tumorigenesis remains unknown.

Ral GDS- and Rho GTPase-mediated pathways

Small GTPases function as critical transducers of extra- and intracellular signals, by cycling between inactive GDP and active GTP bound forms. Ral (A and B) is a member of the Ras subfamily of small GTPases and functions downstream of Ras. Ras-GTP recruits guanine nucleotide exchange factor for Ral (Ral-GEF) to the plasma membrane, which then promotes membrane localization of Ral (Wolthuis et al., 1998). The GEF proteins transduce signals by inducing the dissociation of GDP from the respective GTPases and thereby facilitating the binding of GTP. Proteins of the GEF family activate GTPases and are therefore also called guanine nucleotide dissociation stimulator (GDS) family memeber. The guanine nucleotide dissociation stimulator of Ral-GDP (Ral-GDS) also interacts with Ras in a GTP-dependent manner. Therefore, Ras appears to be an upstream effector of the Ral. However, Ras-independent activation of the Ral-GDS/Ral effector pathway is also reported and found to induce cell transformation (Urano et al., 1996; Hofer et al., 1998; Wolthuis and Bos, 1999; Linnemann et al., 2002). Regulation of the Ral-GDS/effector pathway by beta-arrestins mediates cytoskeletal reorganization (Bhattacharya et al., 2002) by activation of Jak/Stat3 pathway and is crucial for mouse myeloid leukemia (Senga et al., 2001).

While Raf and PI3 kinase have emerged as critical regulators of cell growth, development, and apoptosis, less is known about Ral-GDS or Rho. The Ral-GDS has been shown to induce complementary transformation activity of Ras and it is due to a distinct activity different from additive effects on Raf/Erk pathway (White et al., 1996). Similarly, activation of ATF2 (a basic region-leucine zipper transcription factor family member) involved in oncogenic transformation and adaptive responses to viral and genotoxic stress is regulated by an unknown mechanism involving the cooperation between the Ras/Raf/Erk and Ral-GDS/Src/p38 pathways (Ouwens et al., 2002). The Ral-GDS/Ral and PI3 kinase/Akt pathways mediate Ras-regulated activity of choline kinase, whose increased activity is associated with human cancers (Ramirez de Molina et al., 2002). Ral-GDS/Ral effector pathway also activates phospholipase D implicated in cancer metastasis, and critically cooperates with Raf/Erk pathway to promote invasion and metastasis (Ward et al., 2001). Finally, the RalGDS/Ral effector pathway additionally regulates the activity of Ral binding protein (RalBP1), which is also a GTPase activating protein (GAP) for Rho GTPases such as Rac1 and Cdc42 (Jullien-Flores et al. 1995; Yamaguchi et al., 1997; Ikeda et al., 1998). Rac, cdc42, and RhoA are the key members of the family of Rho GTPases that regulate many important processes such as organiztion of actin cytoskeleton, gene transcription, cell cycle progression, membrane trafficking, and cell transformation either by cooperation with Ras/Raf/Erk or PI3 kinase/Akt pathways (Bar-Sagi and Hall, 2000; Sahai and Marshall, 2002; Schmidt and Hall, 2002; Vial et al., 2003). Rac/cdc42 and Rho signaling antagonize each other to control cellular phenotype and migratory behavior (Evers et al., 2000). Downregulation of Rac activity by oncogenic Ras results in enhanced Rho activity and epithelial mesenchymal transition (Zondag et al., 2000).

Both RalGDS and Rho pathways seem to achieve some of their onogenic effects by affecting translational efficiency. Rgr, a homologue of RalGDS, induces cell proliferation, transformation, and gene expression by activating Ras-, Ral-, and Rho- mediated pathways (White et al., 1996; Hernandez-Munoz et al., 2000). Rgr's human orthologue, hRGR, is also frequently altered in a subset of human T-cell malignancies. The 5' UTR of wild-type Rgr contains eight upstream start codons in a manner similar to mRNAs encoding oncoproteins and growth factors involved in abnormal signaling in tumorigenesis. The 5' UTR exerts a strong inhibitory control on its own translation, and activation of the Rgr oncogene to confer its transforming ability occurs by elimination of its translational regulatory elements (Hernandez-Munoz et al., 2003). This is consistent with the human T-cell malignancies, where high-level expression of truncated forms of hRGR gene is observed (Leonardi et al., 2002). Reorganization of actin cytoskeleton is considered important for not only the Rho-dependent regulation of gene expression through factors such as serum response elements in 3'UTRs (Witteck et al., 2003). Autoregulation in the synthesis of actin itself requires the 3'UTR of the mRNA (Lyubimova et al., 1999), suggesting translational control in Rho GTPase effectors. Further, Rho activity has also been shown to inhibit the translation efficiency of p27Kip1 mRNA and the Rho responsive element lies within a 300 nt region at the 3'end of the mRNA (Vidal et al., 2002). Thus, RalGDS/Rho GTPase mediated pathways also contribute to oncogenic modulation of translational control.

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Global analysis of molecular signatures in cancer through translationally regulated oncogenes

Many studies have identified the role of differential gene expression in complex biological processes (Pollack et al. (2002)). Amidst various available methods such as differential display, subtractive cDNA cloning, serial analysis of gene expression (SAGE), and comparative genomic hybridization (CGH), global gene expression profiling with microarrays has been a very powerful tool in capturing a comprehensive and biologically meaningful molecular signature for a given pathophysiological phenotype. Several cancer types have been molecularly classified based on global transcriptome analysis of total cellular mRNA levels.

Microarray profiling of cancer and oncogenic signaling

Gene expression profiling of total cellular mRNA has been successfully used to identify different cancer types, classify tumors, measure the effects of oncogenic signaling pathways, and identify novel therapeutic targets and molecular diagnosis. Recently, gene expression arrays are also developed for clinical cancer outcome, and patient management (Pomeroy et al., 2002; Chen et al., 2003; Pedersen et al., 2003; Sotiriou et al., 2003). Distinct gene expression signatures help to identify low-grade astrocytoma, glioblastoma, and oligodendroglioma subtypes of brain tumors (Shai et al., 2003; van den Boom et al., 2003). Similarly, six clear cell carcinomas were distinguished from other ovarian carcinomas, grade I and Grade II from Grade III serous papillary carcinoma and ovarian from breast carcinomas (Schaner et al., 2003). Expression profiling also accurately identified prognostic subtypes of pediatric acute lymphoblastic leukemia (Ferrando et al., 2003; Ross et al., 2003), combinatorial versus single drug treatment (combination chemotherapy) responsive specific changes in gene expression in human leukemia (Cheok et al., 2003), human lung adenocarcinoma subclasses (Bhattacharjee et al., 2001), central nervous system embryonal tumor outcome (Pomeroy et al., 2002), distinct gene clusters between malignant and normal plasma cells (De Vos et al., 2002), development of diffuse large B-cell lymphoma, a subclass of non-Hodgkin's lymphoma (Alizadeh et al., 2000), clinical out come of breast cancer (van de Vijver et al., 2002), genes associated with prostate cancer progression (Mousses et al., 2002), and subgroups of human melanoma (Bittner et al., 2000).

DNA microarray gene expression profiling has also assisted in correlating signaling pathways to particular cancer types. For example, transcriptional profiling of the head and neck squamous cell carcinoma identified the interactions between Wnt pathway and Notch pathway components (Ha et al., 2003) and that of the sonic hedgehog (SHH) response identified a critical role for N-myc in neuronal precursor cell proliferation and further the dominant-negative N-myc substantially reduced this response (Oliver et al., 2003). This work also identified cyclin D1 and N-myc as important mediators of SHH pathway. Similarly, previously unrecognized activation of SHH pathway was identified in the derivation of medulloblastomas from cerebellar granule cells (Pomeroy et al., 2002). Microarray analyses were also employed to study the effect of one or limited signaling intermediates of a given signal transduction pathway such as Ras and/or Akt (Rajasekhar et al., 2003), C-Myc (Ellwood-Yen et al., 2003), and Wnt (Willert et al., 2002) in oncogenesis. Metastasis-related genes have also been identified (Ramaswamy et al., 2003) including an essential role of RhoC (Clark et al., 2000) in this process.

Although the above-referenced work clearly shows that this gene expression profiling of total mRNA has been used very successfully in the study of cancer, the abundance of total cellular mRNA does not always correlate well with steady-state levels of the encoded proteins. Thus, microarray analysis may not reliably identify the post-transcriptional changes in protein levels or activity. As the cellular phenotype is determined not by mRNAs, but by the proteins translated by the mRNAs, it is insufficient to know the levels of total cellular transcripts to understand a given phenotype.

Using array technology to describe global recruitment of mRNAs to ribosomes

The eventual outcome of gene expression, protein levels, is regulated at many steps between the gene and the protein. To gain a global view, it is essential to know whether the mRNAs are being translated into cognate proteins, which is in principle a given mRNA's translational state. In fact, eucaryotic gene expression is significantly regulated at the level of translational initiation. Actively translating mRNAs are usually associated with multiple ribosomes and form large structures called polyribosomes or polysomes. Translationally inactive mRNAs are sequestered as messenger ribonucleoprotein (mRNP) particles or associated with a single ribosome (monosome). Thus, the degree of mRNA recruitment to ribosomes is one determinant of relative translational efficiency. Changes in translation initiation rates are common translation-regulating mechanisms resulting in alterations in mRNA loading on ribosomes. Exploitation of this fact resulted in development of a large-scale expression screening for translational control that utilizes the isolation of polysomal RNA and its interrogation by DNA arrays. The experimental methodology involves the separation of polysomes from the free mRNPs using sucrose gradient centrifugation followed by oligonucleotide microarray hybridization. This relies on the principle that actively translating mRNAs are recruited into polysomes and the translationally inactive mRNAs exist as free cytoplasmic mRNPs with significantly lower sedimentation rates. Thus, the global effect of agonists or antagonists that promote these mRNAs in and out of ribosomes can be studied precisely. About 11–13% of the genes were shown to be translationally regulated (activated or repressed) by screening cDNA libraries upon antigenic stimulation of primary human T cells (Mikulits et al., 2000). The early increase in protein synthesis occurred prior to an increase in transcription, and correlated with the mobilization of mRNAs into polysomes (Varesio and Holden, 1980) and activation of translation initiation components (Cohen et al., 1990; Welsh et al., 1996).

The power of polyribosomal RNA expression profiling was extended to situations where translation initiation factor-independent recruitment of polyribosomes to mRNAs occur. For example, RNA viruses proteolytically cleave eiF-G destabilizing the formation of eif-F complex and inhibit cap-dependent translation in the host, but do not affect the viral mRNA-mediated protein synthesis from their 5' noncoding region (5'NCR). The 5'NCR contains an IRES that recruits 40S ribosomal subunit in the absence of intact eiF-4F. Expression analysis of polysomal RNA isolated from poliovirus-infected HeLa cells facilitated the identification of eucaryotic mRNAs that are translated at a reduced concentrations of cap binding eiF-4F complex (Johannes et al., 1999). Approximately 200 of the 7000 mRNAs remained associated with the polyribosomes and represented immediate early transcription factors, kinases, phosphatases, and several proto-oncogenes that have been previously identified to have roles in inflammation and angiogenesis (Iyer et al., 1999). It is interesting to note that under the same eiF-4F- limiting conditions, the mRNA encoding Cyr61, a secreted factor that can promote motility, angiogenesis, and tumor growth, was selectively loaded with polyribosomes without changes in its overall RNA abundance (Johannes et al., 1999). More interestingly, translation of another mRNA encoding Pim-1, which cooperates with c-myc in cellular transformation, was identified to be cap-independent under these conditions.

Global and specific translational analysis of the RNA profile response in Saccharomyces cerevisiae to a rapid transfer from glucose to glycerol resulted in a loss of polysome- associated mRNAs encoding ribosomal proteins in a manner analogous to the 5' oligopyrimidine (5'TOP) sequence containing mammalian ribosomal protein coding mRNAs upon serum starvation (Kuhn et al., 2001). This observation is of particular interest as yeast ribosomal proteins do not contain 5'TOP sequences and 3' untranslated regions of the yeast ribosomal proteins are thought to determine the ribosomal loading function. These studies have identified two novel genes whose transcripts are preferentially mobilized into polysomes, while the overall translation initiation of newly synthesized and pre-existing mRNAs was generally repressed after the shift in carbon source.

Polysome profiling and oncogenic signaling

Comparison of total and polysome RNA profiling has been used to normalize the loading efficiency of mRNAs to ribosomes. This approach compares microarray profiling of both total and polysome-associated mRNAs and has been used to determine the effects on translation of combined Ras and Akt signaling in glia. Such normalized polyribosomal RNA (NPR) values are characteristic of a given cell type at a specific signaling state. Comparison between the NPRs of two cell types or between cells with or without signaling blockade generates comparative normalized polysomal RNA (CNPR) (For details see Figure 1) (Rajasekhar et al., 2003). These two signaling pathways were investigated in glia because combined Ras and Akt signaling is found in human glioblastomas and causally related to the formation of glioblastomas in mice (Holland et al., 2000; Begemann et al., 2002). CNPR was measured as a function of the activity of the Ras and Akt signaling pathways in cell culture (Figure 2). At 2 h of pharmacologic signal blockade of either Ras or Akt pathways, the fold-increase in polysome recruitment for a specific subset of mRNAs far exceeded the fold changes in the total mRNA for any gene represented on the array. The mRNAs so affected encode proteins promoting signal transduction, cell cycle progression, cell motility, and other functions known to be involved in oncogenesis and/or in gliomagenesis. Therefore, part of the oncogenic effect of combined Ras and Akt signaling appears to be due to differential recruitment of existing mRNA into polysomes resulting in altered production of growth-regulating and oncogenic proteins (Rajasekhar et al, 2003). It is not known if these alterations in the translational efficiency of existing mRNAs are sufficient to induce tumor formation and required for its maintenance.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Normalization of polyribosomal RNA. Total cellular and polysome RNAs were analysed by microarray analysis. A pair-wise comparison between a total RNA and its corresponding polysomal RNA was made to obtain the relative ribosomal loading of all mRNAs, referred to normalized polyribosomal RNA (NPR) (Rajasekhar et al., 2003)

Full figure and legend (154K)

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Regulation of translation initiation by growth factor receptor-induced signal involving activated Ras/ERK and PI3K/Akt kinase pathways. Both pathways involve sequential phosphorylation of downstream components as indicated by pink circles. Growth factor receptor stimulation of PI3 kinase results in serial activation of PDK, Akt, and mTOR, leading to phosphorylation of S6RP via S6 kinase and phosphorylation of 4EBPs. Ras sequentially activates a kinase cascade Raf1, MEK, ERK and ultimately eIF4E levels. The pathways cooperate to regulate eiF4E activity and thereby modify the translational effect of existing mRNAs, encoding growth-regulated proteins

Full figure and legend (242K)

Global gene expression at the single cell level and ribonomic profiling

All of the studies listed so far have been analyses of cell populations; the ribosomes are assumed to be a homogenous collection of particles. However, there is no particular reason to believe that within a given cell all of the ribosomes equally translate any given mRNA species. It is at least conceivable that ribosomes exist as a heterogeneous population and that certain ribosomes have a predilection for certain messages. In fact, some studies hint that this may be the case. Recently, mRNA subsets were identified in mRNP complexes using antibodies to RNA binding proteins and genomic arrays. The consequent analyses is referred to as 'ribonomics' (Keene, 2001; Tenenbaum et al., 2002). The ribonomic profiling reduces the complexity of standard gene expression analysis as it yields only a subset of steady-state mRNAs. For example, using mRNA binding proteins such as Hu, eiF-4E, and PABP, different mRNPs were identified from P19 embryonal carcinoma stem cells. The mRNA profiles associated with each of these were unique and represented gene clusters that differed from total cellular RNA (Tenenbaum et al., 2000).

Not only could there be different subsets of ribosomes within a given cell that prefer specific mRNAs, these ribosomes may physically cluster giving rise to regions within the cell that produce certain subsets of the proteome. Thus, the physical organization of the transcripts may be critical and depend on mRNA's stability, abundance, localization, and characteristics of the other associating proteins. The proteins encoded by physically clustered mRNAs may participate in the related biological processes or structural outcomes similar to operons and their polycistronic mRNAs in procaryotic systems (Keene and Tenenbaum, 2002). It remains to be explored if the mRNPs represent some of the means by which multicellular organisms preserve the dynamics of genetic complexity.

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Concluding remarks

Translational control appears to be a major regulatory step in normal and abnormal cell growth, cell proliferation, cancer initiation, and metastasis. Signaling by oncogenic pathways affects the production of specific proteins by regulating the translational efficiency of their mRNAs. Components of the translation machinery appear to have a primary and early impact on the emergence of malignant phenotype as observed by rapid changes in the relative recruitment of existing mRNAs into polysomes. This effect on translation precedes the transcriptional response, thus oncogenic signaling appears to put translation before transcription in oncogenesis (Lasko, 2003; Prendergast, 2003). By coordinately modulating malignancy-related proteins, eiF-4E and its antagonists, the 4E-BPs play a pivotal role in regulating oncogenesis.

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Acknowledgements

We thank Christina Glaster for her expertise in preparing this manuscript. This work was supported by NIH Grants UO1CA894314, RO1CA94842, and RO1CA099489, and the Seroussi, Tow, Searle, and Bressler Scholars foundations.

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