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• W1978592004 abstract "Gene expression in the eukaryotic cell is regulated at a number of levels, including transcription of genomic DNA into messenger RNA (mRNA), nucleocytoplasmic export of mRNA, and translation of the exported mRNA into proteins in the cytoplasm by ribosomes. The role played by epigenetics and transcription factors associated with the control of gene expression in the developing neutrophil has been well documented and appreciated over the years. A wealth of information on the role played by transcription factors in myeloid biology has contributed to our understanding of both normal and abnormal neutrophil development. However, regulation of mRNA translation in myeloid cell maturation is much less well-studied. A better understanding of the translational control of myeloid gene expression may provide important insights into both normal and abnormal myeloid maturation. This review summarizes our current understanding of the regulation of myeloid gene expression at the mRNA translational level. Gene expression in the eukaryotic cell is regulated at a number of levels, including transcription of genomic DNA into messenger RNA (mRNA), nucleocytoplasmic export of mRNA, and translation of the exported mRNA into proteins in the cytoplasm by ribosomes. The role played by epigenetics and transcription factors associated with the control of gene expression in the developing neutrophil has been well documented and appreciated over the years. A wealth of information on the role played by transcription factors in myeloid biology has contributed to our understanding of both normal and abnormal neutrophil development. However, regulation of mRNA translation in myeloid cell maturation is much less well-studied. A better understanding of the translational control of myeloid gene expression may provide important insights into both normal and abnormal myeloid maturation. This review summarizes our current understanding of the regulation of myeloid gene expression at the mRNA translational level. Translation of eukaryotic messenger RNAs (mRNAs) into proteins is a highly regulated and complex process (reviewed in [1Van Der Kelen K. Beyaert R. Inzé D. De Veylder L. Translational control of eukaryotic gene expression.Crit Rev Biochem Mol Biol. 2009; 44: 143-168Crossref PubMed Scopus (95) Google Scholar]). After transcription, mRNA is spliced, capped at the 5′ end, and polyadenylated at the 3′ end. It then undergoes export from the nucleus to the cytoplasm to allow the initiation of translation to begin. Translation can be divided into three major sequential steps: initiation, elongation, and termination. Because translation initiation has been shown to be a critical rate-limiting step in mediating cellular protein synthesis, the current review will focus on that phase of translation. Translation initiation in eukaryotes involves approximately 10 initiation factors designated eukaryotic initiation factors (eIFs). Translation initiation begins when the factors eIF-1, eIF-1A, and eIF-3 bind to the 40S ribosomal subunit. EIF-2 (in a complex with GTP) associates with the initiator methionine-transfer RNA (tRNAiMet). The eIF-4 family of factors then brings the mRNA to be translated into contact with the 40S ribosomal subunit. The 40S ribosomal subunit, now loaded with the bound methionyl initiator tRNA and eIFs, scans the mRNA to locate the AUG initiation codon. When the AUG codon is reached, eIF-5 triggers the hydrolysis of GTP bound to eIF-2. All the initiation factors are then released, and a 60S subunit binds to the 40S subunit to form the 80S initiation complex; elongation and termination then proceed, resulting in the synthesis of a new polypeptide chain. Little is known about the specific roles played by many of these factors during myeloid maturation. However, it is known that the delicate balance that controls translation initiation is often lost in malignancy. For example, overexpression of the eIF4-E factor resulting in increased proliferation has been observed in the bone marrow of patients in the blast crisis phase of chronic myelogenous leukemia and also in patients with acute myelogenous leukemia. Thus, the critical role of translation initiation in regulating protein synthesis and cell proliferation makes translation initiation factors potential therapeutic targets for the treatment of myeloid malignancies. The recruitment of the 40S ribosomal subunit to the 5′ end of mRNA is a crucial, complex, and rate-limiting step during 5′ cap-dependent translation. Cap-binding protein eukaryotic initiation factor 4E (eIF4E) recognizes and binds to the m7GpppN cap (where m is a methyl group and N any nucleotide) structure at the 5′ end of the mRNA. Under basal conditions, eIF4E remains bound to 4E-binding proteins (4E-BPs), blocking translation. However, phosphorylation of the 4E-BPs by means of signal transduction pathways regulated by growth factors and nutrient status, releases the 4E-BPs from eIF4E (Fig. 1A ). This in turn allows the competing eIF4G scaffold protein to bind to eIF4E. eIF4G then recruits the adenosine triphosphate−dependent RNA helicase eIF4A (eIF4E, 4G, and 4A are collectively referred to as eIF4F in the literature), the ubiquitously expressed cofactor eIF4B as well as eIF3, a multisubunit initiation factor, which binds to the 40S ribosomal subunit (reviewed in [2Sonenberg N. Hinnebusch A.G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets.Cell. 2009; 136: 731-745Abstract Full Text Full Text PDF PubMed Scopus (2139) Google Scholar]) (Fig. 1B). Thus, through its ability to bind mRNA in a sequence nonspecific manner and its interaction with eIF3, eIF4G brings together the mRNA and the 40S ribosomal subunit. The 40S ribosomal subunit in turn must be loaded with the initiator tRNAiMet. This process is facilitated by yet another factor, eIF2. EIF2 binds both the tRNAiMet, as well as GTP giving rise to what is commonly referred to as the ternary complex (Fig. 2). Once the ternary complex associates with the 40S ribosomal subunit, eIF3 and eIF1A, it is referred to as the 43S preinitiation complex (see Fig. 1B).Figure 2Formation and regulation of the ternary complex in eukaryotic translation. The ternary complex is composed of eIf2, GTP, and the initiator methionyl tRNA (iMet). The activity of this complex is modulated by the GTP-exchange factor eIF2B. Stress, amino acid deficiency and heme deficiency result in the activation of the eIF2 kinases, which phosphorylate the α-subunit of eIF2. Phosphorylated eIF2α binds eIF2B with high affinity, thereby preventing GTP/GDP exchange. Because levels of eIF2B are limiting in the cell, the net result is a reduction in translation initiation via lowered levels of the ternary complex.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The preinitiation complex then associates with mRNA by way of eIF3 and eIF4G and the resulting complex is termed the 48S initiation complex. After hydrolysis of the GTP bound to eIF2 to GDP, eIF2 is released and reloaded with another GTP molecule with the aid of the GTP exchange factor eIF2B for another round of initiation (Fig. 2). The 40S subunit now scans the mRNA in a 5′ to 3′ direction in search of the first in-frame translation initiation AUG codon. Once this is encountered and a codon−anticodon interaction established, the initiation factors dissociate from the 40S ribosomal subunit allowing for the binding of the large ribosomal 60S subunit and polypeptide synthesis ensues (Fig. 1B). In addition to eIF4F, other factors are also involved in the stabilization of the ribosome−mRNA interactions. These include the polyA-binding protein, which binds at the 3′ end of mRNA and promotes mRNA-ribosome stabilization through its loop-back interaction with eIF4G. In addition, eIF4B and eIF4H are RNA chaperones that assist in mRNA secondary structure unwinding activity of eIF4A [3Sonenberg N. Dever T.E. Eukaryotic translation initiation factors and regulators.Curr Opin Struct Biol. 2003; 13: 56-63Crossref PubMed Scopus (270) Google Scholar]. Translation control occurs largely by the regulation of the activity and integrity of the cap-dependent translation initiation complex (reviewed in [1Van Der Kelen K. Beyaert R. Inzé D. De Veylder L. Translational control of eukaryotic gene expression.Crit Rev Biochem Mol Biol. 2009; 44: 143-168Crossref PubMed Scopus (95) Google Scholar]). In general, translation initiation is regulated by two major mechanisms. The first, illustrated in Figure 1A, involves a group of proteins termed 4E-BPs (eIF4E binding proteins), which compete with eIF4G to bind to the 5′ cap-associated eIF4E protein. However, the 4E-BPs are phosphorylated upon activation of the phosphoinositol-3-kinase (PI3K) pathway and its downstream target mTOR (mechanistic or mammalian target of rapamycin) [4Gingras A.C. Raught B. Sonenberg N. Regulation of translation initiation by FRAP/mTOR.Gene Dev. 2001; 15: 807-826Crossref PubMed Scopus (1159) Google Scholar]. The second mechanism involved in the control of translation initiation is mediated by the phosphorylation of the eIF2α subunit on serine 51 by the four known eIF2α kinases, resulting in global translational arrest. Both these mechanisms are detailed here. The mTOR pathway is an evolutionarily conserved pathway that is critical for cellular responses to environmental cues. mTOR (mechanistic/mammalian target of rapamycin) is a serine/threonine protein kinase belonging to the PIKK family of protein kinases (reviewed in [5Ma X. Blenis J. Molecular mechanisms of mTOR mediated translational control.Nat Rev Mol Cell Biol. 2009; 10: 307-318Crossref PubMed Scopus (1827) Google Scholar]). Mammalian TOR is a functional component of two distinct multiprotein complexes, mTORC1: in which mTOR is complexed with raptor (regulatory protein of mTOR) and LST8 (also called GβL), and mTORC2, harboring both LST8 and rictor. mTORC1 has been shown to be responsive to the inhibitory effects of the antibiotic rapamycin, while mTORC2 is not [6Wullschleger S. Loewith R. Hall M.N. TOR signalling in growth and metabolism.Cell. 2006; 124: 471-484Abstract Full Text Full Text PDF PubMed Scopus (4526) Google Scholar]. mTORC1 functions as a multimeric protein complex that regulates protein synthetic pathways responsive to nutritional-, environmental-, and growth factor−mediated signals. The phosphotransferase activity of mTORC1 is modulated by the activation of RHEB (Ras homolog enriched in brain; a GTP-GDP exchange protein), which in turn is regulated by a heterodimeric tumor suppressor containing the proteins tuberous sclerosis 1 (TSC1) and TCS2. The latter is a GTPase-activating protein, which can modulate the activity of RHEB by converting it to its GDP-bound inactive form [7Martin K.A. Blenis J. Coordinate regulation of translation by the PI3-kinase and mTOR pathways.Adv Cancer Res. 2002; 86: 1-39Crossref PubMed Scopus (174) Google Scholar]. The two major targets of mTOR are the 4E-BPs and the 40S ribosomal protein S6 kinases (S6K), both important components of the translational machinery. Upon activation, mTOR regulates the phosphorylation/activation of p70 S6 kinase (S6K) and the phosphorylation/deactivation of 4E-BP1 [8Platanias L.C. Mechanisms of type-1 and type-II interferon-mediated signaling.Nat Rev Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2175) Google Scholar]. Activation of S6K is thought to modulate ribosome biogenesis through the activation of ribosomal protein S6 [9Lee-Fruman K.K. Kuo C.J. Lippincott J. Terada N. Blenis J. Characterization of S6K2, a novel kinase homologous to S6K1.Oncogene. 1999; 18: 5108-5114Crossref PubMed Scopus (117) Google Scholar] (Fig. 3). In addition, S6K also phosphorylates eIF2B, SKAR (S6K1 Aly/REF-like target), and eukaryotic elongation factor 2 kinase, thus affecting both the initiation and elongation stages of mRNA translation. Hypophosphorylation of the 4E-BPs is thought to increase their affinity for eIF4E, thus blocking binding of the eIF4G and eIF4A and hampering translation initiation of mRNA from proceeding (Fig. 1A). However, phosphorylation of the 4E-BPs by the PI3K-mTOR signaling pathway (Fig. 3) results in lowered affinity of these proteins for eIF4E, thereby allowing for the formation of the competing eIF4E-eIF4G-eIF4A (eIF4F)-mRNA complex that permits mRNA translation to proceed [4Gingras A.C. Raught B. Sonenberg N. Regulation of translation initiation by FRAP/mTOR.Gene Dev. 2001; 15: 807-826Crossref PubMed Scopus (1159) Google Scholar]. Thus, inhibition of mTOR activity results in downregulation of the activity of several components of the translational machinery resulting in a block in cell proliferation and eventually to cell death. A recent study in which the 4E-BP1 and 4E-BP2 genes were ablated in mice surprisingly demonstrated an impairment of myelopoiesis with no apparent effect on thymocyte maturation [10Olson K. Booth G.C. Poulin F. Sonenberg N. Beretta L. Impaired myelopoiesis in mice lacking the repressors of translation initiation, 4E-BP1 and 4E-BP2.Immunology. 2009; 128: e376-e384Crossref PubMed Scopus (11) Google Scholar]. These mice exhibited an increase in the number of immature granulocytic precursors and a concomitant decrease in the numbers of mature granulocytes compared to their wild-type littermates. It has been previously shown in in vitro cell culture studies that expression of the 4E-BPs is markedly increased during granulopoiesis [11Grolleau A. Sonenberg N. Wietzerbin J. Beretta L. Differential regulation of 4E-BP1 and 4E-BP2, two repressors of translation initiation, during human myeloid cell differentiation.J Immunol. 1999; 162: 3491-3497PubMed Google Scholar]. Based on these observations, it was concluded that 4E-BP1 and 4E-BP2 play a pivotal role in the early phases of granulomonocytic differentiation, thus underscoring the role of translation initiation during granulopoiesis. In this context, 4E-BP1 has been shown to be constitutively phosphorylated in both chronic myeloid leukemia (CML) and in acute myeloid leukemia (AML) as a result of constitutive activation of mTOR and Bcr-Abl in CML [12Ly C. Arechiga A.F. Melo J.V. Walsh C.M. Ong S.T. Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia via the mammalian target of rapamycin.Cancer Res. 2003; 63: 5716-5722PubMed Google Scholar] and PI3K-Akt in AML [13Xu Q. Simpson S.E. Scialla T.J. Bagg A. Carroll M. Survival of acute myelod leukemia cells requires PI3 kinase activation.Blood. 2003; 102: 972-980Crossref PubMed Scopus (419) Google Scholar]. Upregulation of eIF4E is sufficient to drive protein translation and to transform cells. Previous work has demonstrated an overexpression of eIF4E in bone marrow mononuclear cells from patients with AML. Upregulation of a subclass of proto-oncogenes that have been referred to as eIF4E-sensitive, including c-myc, cyclin D1, and Bcl-xl [14Culjkovic B. Topisirovic I. Skrabanek L. Ruiz-Gutierrez M. Borden K.L. eIF4E is a central node of an RNA regulon that governs cellular proliferation.J Biol Chem. 2006; 175: 415-426Google Scholar], is thought to contribute to the underlying pathology of AML. The mTORC1 axis plays an important role in controlling factors associated with cellular processes that have commonly gone awry in human cancers, including AML (reviewed in [15Hagner P. Schneider A. Gartenhaus R.B. Targeting the translational machinery as a novel treatment strategy for hematologic malignancies.Blood. 2010; 115: 2127-2135Crossref PubMed Scopus (82) Google Scholar]). Additionally, both upstream (e.g., AKT) and downstream (e.g., eIF4E) mediators within the mTORC1 pathway have been shown to be mutated in hematopoietic and other malignancies. Constitutive activation of mTORC1 has been reported in all cases of AML, while only 50% of AML patients have mutation in the PI3K/AKT pathway. The mechanism underlying the activation of mTORC1 is thus not fully understood [16Park S. Chapiuis N. Tamburini J. et al.Role of the PI3K/AKT and mTOR pathways in acute myeloid leukemia.Haematologica. 2010; 95: 819-828Crossref PubMed Scopus (198) Google Scholar]. This pathway is therefore viewed as an important potential target for therapeutic strategies for leukemia, lymphoma, and multiple myeloma. In this context, the use of rapamycin (mTORC1 inhibitor, see Fig. 3), its analogs (rapalogs) and second-generation derivatives are at different stages of preclinical investigation or are in clinical trials (reviewed in [15Hagner P. Schneider A. Gartenhaus R.B. Targeting the translational machinery as a novel treatment strategy for hematologic malignancies.Blood. 2010; 115: 2127-2135Crossref PubMed Scopus (82) Google Scholar]). In a recent study, Tamburini et al. showed that rapamycin did not consistently inhibit protein translation in AML cells. The authors did show however, that the 4E-BP1 memetic 4EGI-1 did inhibit translation of the eIF4E-sensitive oncogenes, including c-myc and cyclin D1 and induced cell death of AML cells in culture. This study demonstrated that protein translation in AML cells is regulated by an mTORC1-independent, 4E-BP1/eIF4E-dependent pathway [17Tamburini J. Green A.S. Bardet V. et al.Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia.Blood. 2009; 114: 1618-1627Crossref PubMed Scopus (156) Google Scholar]. A better understanding of these pathways is clearly warranted and will likely provide a more objective roadmap to the rational development of improved therapies for AML. Regulation of tRNAimet binding step during mRNA translation, a second rate limiting step in translation initiation, occurs independently of the mTOR pathway (Fig. 2). Phosphorylation of the α subunit of eIF2 on serine 51 by stress-induced enzymatic activity of four known kinases: heme-regulated inhibitor (HRI), protein kinase R (PKR), protein kinase R−like endoplasmic reticulum-associated eIF2α kinase (PERK), and mammalian general control non-derepressing 2 (mGCN2), transforms eIF2 from a substrate for the guanine exchange factor eIF2B to a competitive inhibitor [18Hinnebusch A. Mechanism and regulation of initiator methionyl-tRNA binding to ribosomes.in: Sonnenberg N. Hershey J.W.B. Mathews M.B. CSH monographs volume 39: translational control of gene expression. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2000: 185-243Google Scholar]. This is because phosphorylated eIF2α has a higher affinity for eIF2B than unphosphorylated eIF2α. This results in the sequestering of eIF2B, thus preventing it from functioning as a guanine nucleotide exchange factor (Fig. 2). The resultant reduction in levels of the ternary complex causes global inhibition of translation. Limiting levels of eIF2B in the cell make this a critical regulatory factor in contributing to global translational regulation within the cell [19Oldfield S. Jones J. Tanton D. Proud C. Use of monoclonal antibody to study the structure and function of eukaryotic protein synthesis initiation factor eIF2B.Eur J Biochem. 1994; 221: 399-410Crossref PubMed Scopus (46) Google Scholar]. Approximately 10% of vertebrate mRNAs possess specialized cis-regulatory elements that make them specifically responsive to translational control. This feature allows for a subgroup of mRNAs to be translated in the wake of global translational arrest in response to environmental stress. mRNAs endowed with these cis-elements, which include upstream initiation codons, upstream open-reading frames (uORFs) and internal ribosome entry sites, include key regulatory proteins, cytokines, growth factors, and components of the cell cycle, the expression of which is necessary to return the cell to homeostasis. Examples of such mRNAs include cyclin D1 [20Rousseau D. Kaspar R. Rosenwald I. Gehrke L. Sonenberg N. Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E.Proc Natl Acad Sci U S A. 1996; 93: 1065-1070Crossref PubMed Scopus (353) Google Scholar], thrombopoietin [21Ghilardi N. Wiestner A. Skoda R.C. Thrombopoietin production is inhibited by a translational mechanism.Blood. 1998; 92: 4023-4030Crossref PubMed Google Scholar], BCL-2 [22Harigai M. Miyashita T. Hanada M. Reed J.C. A cis-acting element in the BCL-2 gene controls expression through translational mechanisms.Oncogene. 1996; 12: 1369-1374PubMed Google Scholar], the myeloid master transcriptional regulator CCAAT/enhancer binding protein−α (C/EBPα) and its family member C/EBPβ [23Calkhoven C. Müller C. Leutz A. Translational control of C/EBPalpha and C/EBPbeta isoform expression.Gene Dev. 2000; 14: 1920-1932PubMed Google Scholar], among others. C/EBPα is the founding member of a family of basic region/leucine zipper transcription factors and has been shown to be a master regulator of granulopoiesis (reviewed in [24Mueller B.U. Pabst T. C/EBPa and the pathophysiology of acute myeloid leukemia.Curr Opin Hematol. 2006; 13: 7-14Crossref PubMed Google Scholar, 25Schuster M. Porse B. C/EBPa: a tumour suppressor in multiple tissues?.Biochim Biophys Acta. 2006; 1766: 88-103PubMed Google Scholar, 26Fuchs O. Growth-inhibiting activity of transcription factor C/EBPa, its role in hematopoiesis and its tumour suppressor or oncogenic properties in leukaemias.Folia Biologica (Praha). 2007; 53: 97-108PubMed Google Scholar, 27Koschmieder S. Halmos B. Levantini E. Tenen D.G. Dysregulation of the C/EBPalpha differentiation pathway in human cancer.J Clin Oncol. 2009; 27: 619-628Crossref PubMed Scopus (162) Google Scholar]). It is expressed at high levels throughout myeloid differentiation and has been shown to bind to the promoters of multiple myeloid-specific genes at different stages of myeloid maturation [24Mueller B.U. Pabst T. C/EBPa and the pathophysiology of acute myeloid leukemia.Curr Opin Hematol. 2006; 13: 7-14Crossref PubMed Google Scholar, 25Schuster M. Porse B. C/EBPa: a tumour suppressor in multiple tissues?.Biochim Biophys Acta. 2006; 1766: 88-103PubMed Google Scholar, 26Fuchs O. Growth-inhibiting activity of transcription factor C/EBPa, its role in hematopoiesis and its tumour suppressor or oncogenic properties in leukaemias.Folia Biologica (Praha). 2007; 53: 97-108PubMed Google Scholar]. Profound hematopoietic abnormalities have been reported for mice nullizygous for C/EBPα [28Zhang P, Iwama A, Datta MW, Darlington GJ, Link DC, Tenen DG. Granulocyte development in C/EBP-alpha-/-mice: the role of expression of the IL-6 and G-CSF receptors. 39th Annual Meeting of the American Society of Hematology, San Diego, CA, December 1997; p. 90.Google Scholar]. Although C/EBPα−/− mice die perinatally due to defects in gluconeogenesis that result in fatal hypoglycemia [29Wang N.D. Finegold M.J. Bradley A. et al.Impaired energy homeostasis in C/EBP-alpha knockout mice.Science. 1995; 269: 1108-1112Crossref PubMed Scopus (825) Google Scholar], they also have a selective early block in the differentiation of granulocytes. The C/EBPα gene is intronless and generates two isoforms as a result the differential utilization of alternate translation start codons. The resultant p42kD (full length) and p30kD (truncated) C/EBPα proteins differ from each other at the N-terminus, which is abbreviated in the p30kD protein (see Fig. 4). Translational control of C/EBPα-isoform expression is orchestrated by a conserved cis-regulatory uORF in the 5′UTR (untranslated region) that is out of frame with the coding region of C/EBPα and is thought to be responsive to the activities of both eIF4E and eIF2 (Fig. 4). Thus, an increase in the activity of eIF2 or eIF4E, as may be expected during neoplastic cell proliferation, results in the increase in expression of the shorter p30 isoform (reviewed in [23Calkhoven C. Müller C. Leutz A. Translational control of C/EBPalpha and C/EBPbeta isoform expression.Gene Dev. 2000; 14: 1920-1932PubMed Google Scholar]). As is indicated in Figure 4, a small uORF monitors the site of translation initiation by sensing the activity of the translation initiation factors eIF2 and eIF4E. When levels of these factors are high, the out-of-frame uORF is translated, but termination of its translation very close to the AUG for p42 is thought to prevent reinitiation at AUG1. Instead, ribosomes continue to scan and reinitiate at AUG2, resulting in the expression of C/EBPα p30. In contrast, under basal conditions, when levels of the initiation factors are relatively low, most ribosomes do not initiate translation at the uORF, but instead initiate translation at AUG1 by a process involving “leaky ribosome scanning,” resulting in translation of the full-length C/EBPα p42 isoform [23Calkhoven C. Müller C. Leutz A. Translational control of C/EBPalpha and C/EBPbeta isoform expression.Gene Dev. 2000; 14: 1920-1932PubMed Google Scholar]. This mechanism of translational control appears to be conserved among key regulatory proteins, which govern differentiation and proliferation. It has been hypothesized that expression of mRNAs encoding these key regulatory proteins that determine cell fate are translated only at permissive levels of the translation initiation factors eIF2 and eIF4E, which in turn are responsive to environmental and other cues. Under these conditions, via an uORF-mechanism, the ratios of the different isoforms of these key regulatory proteins is adjusted to allow for either proliferation or differentiation [23Calkhoven C. Müller C. Leutz A. Translational control of C/EBPalpha and C/EBPbeta isoform expression.Gene Dev. 2000; 14: 1920-1932PubMed Google Scholar]. It has been demonstrated that the p30 C/EBPα protein not only interferes with the DNA binding ability of p42 C/EBPα, thus inhibiting transactivation of key granulocytic target genes in a dominant-negative manner [30Pabst T. Muller B. Zhang P. Dominant negative mutations of CEBPA encodong CCAAT/enhancer binding protein-a (C/EBPa), in acute myeloid leukemia.Nat Genet. 2001; 27: 263-270Crossref PubMed Scopus (722) Google Scholar], but also binds to the promoters of a distinctive set of target genes to alter their transcription [31Geletu M. Balkhi M.Y. Peer Zada A.A. et al.Target proteins of C/EBPalphap30 in AML: C/EBPalphap30 enhances sumoylation of C/EBPalphap42 via up-regulation of Ubc9.Blood. 2007; 110: 3301-3309Crossref PubMed Scopus (62) Google Scholar]. Additionally, modification of the mouse locus to express only the p30 isoform led to the formation of granulocyte-macrophage progenitors. However, deficiency of p42 in these mice led to development of AML with complete penetrance [32Kirstetter P. Schuster M.B. Bereshchenko O. et al.Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.Cancer Cell. 2008; 13: 299-310Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar]. Thus, changes in the ratio of p42:p30 isoforms of C/EBPα play a critical role in contributing to AML [33Fu C.T. Zhu K.Y. Mi J.Q. et al.An evolutionarily conserved PTEN-C/EBPα-CTNNA1 axis controls myeloid development and transformation.Blood. 2010; 115: 4715-4724Crossref PubMed Scopus (31) Google Scholar]. Suppression of C/EBPα translation has also been shown to occur in blasts from patients with CML in blast crisis. This is brought about via an RNA binding protein, hnRNP-E2, which binds to the uORF of the C/EBPα mRNA, thereby blocking translation. Expression of hnRNP-E2 is thought to be upregulated by the activity of the oncogenic BCR-ABL fusion protein in CML patients, and downregulation of hnRNP-E2 by the BCR-ABL inhibitor imatinib results in restoration of C/EBPα protein expression and granulocytic differentiation of the CML blasts [34Perrotti D. Cesi V. Trotta R. et al.BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2.Nat Genet. 2002; 30: 48-58Crossref PubMed Scopus (268) Google Scholar]. Examples of regulatory elements within mRNAs that alter translation include microRNA binding elements usually located at the 3′UTR of the mRNA. MicroRNAs (miRNAs) are 18- to 24- nucleotide−long noncoding RNAs that regulate eukaryotic gene expression. miRNAs are encoded in the genome and are initially transcribed by RNA polymerase II as long primary transcripts referred to as primary miRNAs. These transcripts are recognized and processed by a ribonuclease called Drosha into 60 to 80 nucleotide intermediates called precursor miRNAs (pre-miRNAs), which are then exported to the cytoplasm where a second ribonuclease termed Dicer cleaves pre-miRNAs to generate double-stranded 18- to 24-nucleotide−long miRNAs. The miRNAs are then incorporated into the RNA-induced silencing complex (RISC), a large protein complex that also contains the Argonaute or mRNA cleaving proteins. The miRNA guides the RNA-induced silencing complex to target complementary regions in the 3′UTRs of mRNAs, leading to repression of translation or destabilization of the mRNA by deadenylation (reviewed in [35Manikandan J. Aarthi J.J. Kumar S.D. Pushparaj P.N. Oncomirs: the potential role of non-coding microRNAs in understanding cancer.Bioinformation. 2008; 8: 330-334Crossref Google Scholar]). Increasing evidence has implicated miRNAs as components of oncogene and tumor suppressor pathways. Alterations in miRNA expression or structure have been documented in a variety of malignancies [36Lu J. Getz G. Miska E.A. et al.MicroRNA expression profiles classify human cancers.Nature. 2005; 435: 834-838Crossref PubMed Scopus (7986) Google Scholar], and several miRNA families have now been functionally implicated as having tumor-suppressive and oncogenic potential [37Calin G. Dumitru C.D. Shimizu M. et al.Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.Proc Natl Acad Sci U S A. 2002; 99: 15524-15529Crossref PubMed Scopus (4088) Google Scholar, 38He L. Thomson J.M. Hemann M.T. et al.A microRNA polycistron as a potential human oncogene.Nature. 2005; 435: 828-833Crossref PubMed Scopus (3075) Google Scholar]. An increasing body of evidence implicates miRNA activity in mediating both normal and abnormal myelopoiesis (reviewed in [39Pelosi E. Labbaye C. Testa U. MicroRNAs in normal and malignant myelopoiesis.Leukemia Res. 2009; 33: 1584-1593Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]). MiRNAs have, in particular, been shown to activate or be activated by myeloid-specific transcription factors such as C/EBPα and Gfi-1. For example, mir-223 is thought to be a direct target of C/EBPα and its expression increases during granulopoiesis. Ablating mir-223 in mice results in the expansion of granulocyte precursor cells resulting from a cell autonomous increase in the number of granulocytic progenitors [40Johnnidis J. Harris M.H. Wheeler R.T. et al.Regulation of progenitor cell proliferation and granulocyte function by microRNA-223.Nature. 2008; 451: 1125-1129Crossref PubMed Scopus (951) Google Scholar]. Additionally, overexpression of mir-223 in acute promyelocytic leukemia cells results in an enhanced capacity for granulocytic differentiation [41Fazi F. Rosa A. Fatica A. et al.Aminicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis.Cell. 2005; 123: 819-831Abstract Full Text Full Text PDF PubMed Scopus (840) Google Scholar]. Mir-223 is thought to be a positive regulator of granulopoietic differentiation. More recently, it has been shown that mir-223 targets E2F1, a master cell-cycle regulator, by inhibiting translation of its mRNA. Thus, granulopoiesis appears to be regulated by a C/EBPα–miR-223−E2F1 axis, wherein miR-223 functions as a key regulator of myeloid cell proliferation associated with E2F1 in a mutual negative feedback loop [42Pulikkan J. Dengler V. Peramangalam P.S. et al.Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia.Blood. 2010; 115: 1768-1778Crossref PubMed Scopus (231) Google Scholar]. In a paradigm-shifting study, Eiring et al. demonstrated a new role for miRNAs [43Eiring A. Harb J.G. Neviani P. et al.miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts.Cell. 2010; 140: 652-665Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar]. They demonstrated that miR-328 is downregulated in CML patients in blast crisis. Restoration of mir-328 expression, however, restores differentiation by simultaneous interaction with the C/EBPα translational regulator hnRNP-E2 (see above section “Translational control of C/EBPα expression”), as well as with the mRNA for PIM1, a survival factor. Interestingly, the interaction with hnRNP-E2 occurs independently of the microRNAs seed sequence leading to the release of C/EBPα mRNA from hnRNA-E2-mediated translational inhibition. Thus miR-328 appears to control cell fate by its ability to base pair with the 3′UTR of target mRNAs (PIM1), as well as by acting as a decoy for hnRNP binding thus interfering with cell fate by releasing C/EBPα from translational inhibition [43Eiring A. Harb J.G. Neviani P. et al.miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts.Cell. 2010; 140: 652-665Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar]. The role of miR-27 in granulopoiesis has also been documented. This miRNA has been shown to target the myeloid transcription factor AML1, whose expression decreases during granulocytic differentiation in a miR-27−dependent manner. Anti−miR-27 treatment of immature myeloid progenitors resulted in an increase in the expression of AML1 and impaired granulocytic differentiation [44Feng J. Iwama A. Satake M. Kohu K. MicroRNA-27 enhances differentiation of myeloblasts into granulocytes by post-transcriptionally downregulating Runx1.Br J Haematol. 2009; 145: 412-423Crossref PubMed Scopus (69) Google Scholar]. Numerous studies have analyzed the expression of miRNAs in acute myeloid leukemias and the resulting miR signatures generated have proved to be helpful in classifying subtypes of AML and hence the choice of treatment options to be used, as well as in determining the efficacy of targeted therapies against AML. These studies have been detailed elsewhere [39Pelosi E. Labbaye C. Testa U. MicroRNAs in normal and malignant myelopoiesis.Leukemia Res. 2009; 33: 1584-1593Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Neutrophils, monocytes, and macrophages provide the first line of defense against invading organisms or after cellular injury. When activated, these cells secrete antimicrobial agents and cytokines that promote elimination of the invading organisms. However, to prevent overexpression of these toxic agents once the cellular insult has abated, which would otherwise result in a chronic state of inflammation, the cells have developed mechanisms both at the transcriptional and translational levels to turn off cytokine production [45Serhan C. Savill J. Resolution of inflammation: the beginning programs the end.Nat Immunol. 2005; 6: 1191-1197Crossref PubMed Scopus (1712) Google Scholar]. Recent studies have demonstrated that the formation of the so-called GAIT (interferon-γ [IFN-γ] inhibitor of translation) complex at the 3′UTR (untranslated region) of target genes involved in the inflammatory response occurs in myeloid cells (reviewed in [46Mukhopadhyay R. Jia J. Arif A. Ray P.S. Fox P.L. The GAIT system: a gatekeeper of inflammatory gene expression.Trends Biochem Sci. 2009; 34: 324-331Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]). In response to IFN-γ signaling, the tetrameric GAIT complex composed of glutamyl propyl tRNA synthetase (EPRS), NS1-associated protein, ribosomal protein L13a, and glyceraldehyde-3-phosphate dehydrogenase binds defined 3′UTR cis elements within a family of inflammatory mRNAs and suppresses their translation. 3′UTR GAIT elements have been identified in ceruloplasmin (nt 78−106), vascular endothelial growth factor−A (nt 358−386), death-associated protein kinase (nt 1141–1169), zipper-interacting protein kinase (nt 174−206), and chemokine C-C motif ligand 22 (nt 433−462) mRNAs, all associated with the inflammatory response (reviewed in [46Mukhopadhyay R. Jia J. Arif A. Ray P.S. Fox P.L. The GAIT system: a gatekeeper of inflammatory gene expression.Trends Biochem Sci. 2009; 34: 324-331Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]). Two distinct steps are involved in the assembly of the GAIT complex after IFN-γ treatment of myeloid cells. First, approximately 2 hours post−IFN-γ stimulation, EPRS is released from the tRNA multisynthetase complex, where it resides and forms a nonfunctional pre-GAIT complex together with NS1-associated protein. Later, ribosomal protein L13a, which is released from the 60S ribosomal subunit by an unclear mechanism, is joined by glyceraldehyde-3-phosphate dehydrogenase to form a functional GAIT complex at the 3′UTR of the target gene. EPRS is thought to recognize and bind to target mRNAs, NS1-associated protein negatively regulates RNA binding, and L13a binds to and inhibits translation initiation by interacting with eIF4G by competing with eIF3 and the 40S subunit containing 43S preinitiation complex [47Kapasi P. Chaudhuri S. Vyas K. et al.L13a blocks 48S assembly: role of a general initiation factor in mRNA-Specific translational control.Mol Cell. 2007; 25: 113-126Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar] (see Fig. 1B). The dismantling and subsequent reformation of the GAIT complex thus renders the 3′UTR GAIT-regulated mRNAs susceptible to rapid expression in response to cellular insult and later to silencing once the threat has passed. The mechanism underlying the dynamics and release of the four components of the GAIT complex remains under investigation. It is, however, evident that repression of a post-transcriptional regulon by the GAIT system contributes to prevention of chronic inflammation. Control of gene expression at the mRNA translational level has been a particularly neglected area of investigation, especially in myeloid cells. However, a recent surge of interest in this pathway as a result of the realization that cellular pathways commonly deregulated in AML, including cell-cycle progression, proliferation, and differentiation are mechanistically tied to translation. For example, several upstream (AKT, TSC1/2) and downstream (eIF4E) mediators of the mTORC1 pathway are either mutated or activated in AML. Although there has been an intense search for therapeutic strategies targeting the mTOR pathway in myeloid cells, much work has yet to be done to gain a fundamental understanding of the role of the players that contribute to translation initiation and control in normal myeloid cells." @default.
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• W1978592004 title "Regulation and deregulation of mRNA translation during myeloid maturation" @default.
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