{"title":"15 Translational Control in Cancer Development and Progression","authors":"R. Schneider, N. Sonenberg","doi":"10.1101/087969767.48.401","DOIUrl":"https://doi.org/10.1101/087969767.48.401","url":null,"abstract":"Translational control has an important role in key physiological pathways that have a direct impact on cancer development and progression. These include pathways for cell proliferation and growth, cellular responses to stresses such as hypoxia and nutritional deprivation, and stimulation by mitogenic signals (for previous reviews, see Dua et al. 2001; Meric and Hunt 2002; Rosenwald 2004; Holcik and Sonenberg 2005). Consequently, regulation of protein synthesis has emerged as an important component of cancer etiology, both at the level of global control of the proteome and for selective translation of specific mRNAs and classes of mRNAs. What is surprising is how long it has taken to appreciate the central importance and elucidate the key mechanisms of translational control in cancer development and progression. Despite the infancy of this field of research, it is already apparent that translational control of cancer is multifaceted, presenting modifications unique to different types of cancers, as well as different stages and grades of disease. Changes in translation associated with cancer development and progression observed to date involve altered expression of translation components, including translation factors, ribosomes, translation factor regulatory proteins, and tRNAs; altered expression and translation of specific mRNAs; and altered activity of signal transduction pathways that control the activity of protein synthesis, both overall and of individual mRNAs. These changes are manifested in a variety of ways, including up-regulation of global protein synthesis, increased translation of individual mRNAs, and selective translation of antiapoptotic, proangiogenic, proproliferative, and hypoxia-mediated mRNAs. Other transformation-associated changes in translation are...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"3 1","pages":"401-431"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89623640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"17 Translational Control in Metabolic Diseases: The Role of mTOR Signaling in Obesity and Diabetes","authors":"S. Kozma, S. Um, G. Thomas","doi":"10.1101/087969767.48.459","DOIUrl":"https://doi.org/10.1101/087969767.48.459","url":null,"abstract":"For some time it has been recognized not only that protein synthesis is regulated by growth factors and hormonal signaling (Shi et al. 2003), but that the translation machinery is also specifically affected by nutrient levels (Clemens et al. 1980; Pain et al. 1980). These stimuli modulate both the global synthesis of proteins and the selective translation of specific mRNAs. Thus, given the impact of nutrient supply and endocrine signaling on protein synthesis, it is logical to presume that pathological conditions affecting nutrient homeostasis would result in major deregulation of protein synthesis. Currently, the most prevalent homeostatic dis-order is the metabolic syndrome, defined as a cluster of pathologies that always includes obesity, plus at least two of the following factors: raised serum triglyceride levels, reduced high-density-lipoprotein cholesterol levels, raised blood pressure, and raised fasting plasma glucose. The recent dramatic increase in the incidence of obesity has strongly contributed to an escalation of the metabolic syndrome manifestations in Western societies. It is believed that the increase in obesity derives from the fact that during evolution, food scarcity led to the development of dominant genetic traits to secure and manage caloric intake (Neel 1999). In Western societies, food availability, which increased dramatically in the 1950s, began to reveal these calorie-securing traits, and obesity emerged as a prevalent disorder that has since reached epidemic proportions. The nutrient overload resulting from increased food intake is being further accentuated by a decrease in physical activity and a demographic shift to an aging population (Pi-Sunyer 2002).","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"13 1","pages":"459-483"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89178798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"27 Mitochondrial Translation and Human Disease","authors":"E. Shoubridge, F. Sasarman","doi":"10.1101/087969767.48.775","DOIUrl":"https://doi.org/10.1101/087969767.48.775","url":null,"abstract":"Most eukaryotic cells rely on oxidative phosphorylation for cellular ATP production. The machinery for oxidative phosphorylation consists of five large hetero-oligomeric enzyme complexes, located in the inner mitochondrial membrane. The majority of the approximately 85 structural components of this system are encoded in the nuclear genome, but a small number of essential protein subunits—13 in mammals—have been retained on the mitochondrial genome (mtDNA), and these are synthesized on a dedicated protein translation apparatus in the mitochondrial matrix. All of the proteins necessary for the replication, transcription, and translation of the genes encoded in mtDNA are encoded in the nuclear genome. This genetic investment is far out of proportion to the number of proteins involved, and it is likely that a small, semiautonomous mitochondrial genome has persisted because the proteins it encodes are hydrophobic proteins that need to be cotranslationally inserted into the inner mitochondrial membrane during assembly of the oxidative phosphorylation complexes. As might be expected from the α- proteobacterial origins of mitochondria, many of the features of mitochondrial translation are similar to those found in prokaryotes. In this chapter, we review the organization and control of mitochondrial translation, with a particular emphasis on the system in mammals and on mechanisms of disease. ORGANIZATION OF THE MAMMALIAN MITOCHONDRIAL TRANSLATION SYSTEM Mammalian mtDNA is a small (~16.5 kb) double-stranded circular genome that codes for 13 proteins, 22 tRNAs, and 2 rRNAs. It contains no introns, and the genetic code is different from the universal code: Nuclear arginine (AGA, AGG)...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"104 1","pages":"775-801"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88383218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"4 The Mechanism of Translation Initiation in Eukaryotes","authors":"T. Pestova, J. Lorsch, C. Hellen","doi":"10.1101/087969767.48.87","DOIUrl":"https://doi.org/10.1101/087969767.48.87","url":null,"abstract":"Standard translation initiation in eukaryotes is the process that leads to assembly of an 80S ribosome on an mRNA in which the initiation codon is base-paired to the CAU anticodon of aminoacylated initiator methionyl-transfer RNA (Met-tRNA i Met ) in the ribosomal peptidyl (P) site. The process requires separated small (40S) and large (60S) ribosomal subunits and involves at least 12 eukaryotic initiation factors (eIFs) and the binding and hydrolysis of ATP and GTP. The resulting 80S initiation complex is competent to enter the elongation phase of translation. This chapter describes the canonical mechanism of 5′-end-dependent initiation, with a bias toward the initiation process in higher eukaryotes. This process differs in detail from that in plants and yeast, in which the subunit structure and composition of some factors differ substantially. For a more detailed review of initiation in yeast and in plants, see Chapters 9 and 26, respectively. For a review of mechanisms dependent on internal ribosome entry, see Chapters 5 and 6. STRUCTURE OF EUKARYOTIC CYTOPLASMIC mRNAs The translational efficiency of eukaryotic mRNAs is limited by the rate of initiation (see, e.g., Palmiter 1972), which is in turn determined by structural features of mRNAs that influence ribosomal recruitment, scanning to the initiation codon, and initiation codon recognition. Eukaryotic mRNAs associate dynamically with proteins that mediate nuclear export, subcellular localization, stability, and translational repression, and therefore exist in cells as messenger ribonucleoproteins (mRNPs) rather than as free polynucleotides. The influence of mRNP proteins on initiation is outside the scope of this review. Almost...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"1 1","pages":"87-128"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77410334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"21 Regulation of Translation Elongation and the Cotranslational Protein Targeting Pathway","authors":"T. Herbert, C. Proud","doi":"10.1101/087969767.48.601","DOIUrl":"https://doi.org/10.1101/087969767.48.601","url":null,"abstract":"The factors involved in translation elongation are subject to sophisticated control mechanisms that come into play under a wide variety of conditions. Even though translation is most frequently controlled during the initiation phase (Chapter 1) and the regulatory mechanisms impinging on the initiation steps have received considerable attention (reviewed in several chapters of this book), accumulating information points to the elongation phase as a target for controls under defined circumstances. In this chapter, we focus on recent developments in understanding the control of elongation in mammalian cells. As a special case, we also discuss cotranslational protein targeting, a cellular process involving the control of elongation on an important class of mRNAs. REGULATION OF TRANSLATION ELONGATION The mechanism of peptide-chain elongation and the functions of translation elongation factors are described in Chapters 2 and 3. In addition, detailed aspects of the structure and function of eukaryotic elongation factor 2 (eEF2) are the subject of a recent informative review (Jorgensen et al. 2006). eEF2 is a phosphoprotein in mammalian cells, and most of the recent advances relate to the regulation of eEF2 and its cognate kinase, eEF2 kinase. eEF1A and eEF1B also are phosphoproteins and have been discussed in earlier reviews on this subject (Proud 2000; Traugh 2001; Browne and Proud 2002; Le Sourd et al. 2006). Significance of eEF2 Phosphorylation for the Control of Protein Synthesis Under a diverse range of conditions, the phosphorylation state of eEF2 changes in directions consistent with its having a role in regulating protein synthesis; i.e.,...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"23 1","pages":"601-624"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84790023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Afterword Universality and Brain Mechanisms","authors":"R. Greenspan","doi":"10.1101/087969819.49.647","DOIUrl":"https://doi.org/10.1101/087969819.49.647","url":null,"abstract":"In the mid-1980s, when the study of molecular mechanisms in the nervous system first emerged, comparisons between vertebrates and invertebrates began to appear. A fly on the wall of a molecular neurobiology meeting at that time would have heard much talk of “higher” and “lower” organisms. He would have concluded that his cousins, the fruit flies, had evolved from nematodes, and similarly, that frogs had evolved from fruit flies, and likewise mice from frogs. These formulations recalled the Great Chain of Being (Fig. 1), an idea that had strong historical roots dating back to Plato and Aristotle. At one particular neurobiology meeting, a developmental biologist with a strong evolutionary background was asked to give a short summary of phylogeny for the assembled group. He described the two major branches of metazoan evolution, protostomes and deuterostomes (Fig. 1), and tried his best to undo the concepts of “higher” versus “lower,” as well as of a single, continuous line of descent. Over the next two days, it was clear that his discourse was taken as meaning that there was not a single Great Chain of Being; instead, there were actually two. All extant species are certainly not, in fact, evolved directly from each other, but instead represent the currently living products of many different lineage branches. If this is so, then what kinds of meaningful comparisons can we make and what can they tell us? Homologies have traditionally been the goal of evolutionary comparisons. Originally, this meant morphological homology of a structure...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"17 1","pages":"647-649"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85058574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Preface/Front Matter","authors":"G. North","doi":"10.1101/087969819.49.i","DOIUrl":"https://doi.org/10.1101/087969819.49.i","url":null,"abstract":"My coeditor, Ralph Greenspan, and I have decided, rather than to coauthor a preface to this book, to act as bookends, with Ralph writing the Afterword and me writing the Foreword. This does not reflect any disagreement in view, but instead, complementary perspectives. Ralph has the point of view of a professional scientist in the field, and I have the point of view of a professional editor who is most definitely not a specialist, but who finds the field fascinating. Before explaining the rationale and aims of this book, it might be worth giving a bit of background-the views that have informed our approach to the subject.We share the opinion that the molecular revolution which began in the 1950s has over-skewed biology somewhat; the insights into fundamental processes that have been made possible by this revolution are remarkable, but they have tended to foster the view that the main point of biology is to elucidate molecular mechanisms. In the extreme view, a description of any biological phenomenon becomes a mere prelude to analysis by a now well-trod route: Screen for genetic variants where the phenomenon at issue is perturbed; clone the gene; sequence the gene; analyze its product; and so on. This approach has proved tremendously successful in many areas of biology, particularly cellular and developmental biology. Indeed, when the study of the molecular biology of metazoan organisms began in earnest in the 1970s and early 1980s, it was not clear that it would prove quite so...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73177817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"7 Auditory Systems in Insects","authors":"D. Robert, R. Hoy","doi":"10.1101/087969819.49.155","DOIUrl":"https://doi.org/10.1101/087969819.49.155","url":null,"abstract":"Evolution has endowed insects with an extraordinary capacity for miniaturization. Virtually all aspects of insect biology convey the sense of successfully uniting form and function in exquisitely small, diverse, and sophisticated motor, sensory, and metabolic systems (Grimaldi and Engel 2005). The ability of insects to fly in an efficient and controlled manner well illustrates how, through evolution by natural selection, they adapted to solve what we consider serious problems of engineering. Insects are little marvels of “evolutionary engineering.” The seemingly boundless ingenuity and creativity of the process of evolutionary adaptation are also reflected in the sensory systems of insects. As we try to make clear in this chapter, hearing in insects is a sophisticated process; understanding its fundamental mechanisms and trying to understand its evolution present many challenges but are likely to be very rewarding. Perhaps because insects are so small, their ears have generally been considered to be simple compared to those of vertebrates. Anatomically, they may be simpler, but their capacity for sound reception and processing turns out to be remarkably elaborate (for reviews, see Fullard and Yack 1993; Hoy 1998; Robert and Gopfert 2002; Robert 2005; Hedwig 2006; Gopfert and Robert 2007). The ears of insects can be as sensitive and acute as their vertebrate counterparts (Webster et al. 1992; Hoy 1998). Indeed, in some cases their feats of detection surpass the capabilities of vertebrates (Robert and Gopfert 2002). For example, the ultrafast ears of the parasitoid fly Ormia ochracea can distinguish time differences in the arrival...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"90 1","pages":"155-184"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75436149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"1 Origins and Principles of Translational Control","authors":"M. Mathews, N. Sonenberg, J. Hershey","doi":"10.1101/087969767.48.1","DOIUrl":"https://doi.org/10.1101/087969767.48.1","url":null,"abstract":"Proteins occupy a position high on the list of molecules important for life processes. They account for a large fraction of biological macromolecules—about 44% of the human body’s dry weight, for example (Davidson et al. 1973)—they catalyze most of the reactions on which life depends, and they serve numerous structural, transport, regulatory, and other roles in all organisms. Accordingly, a large proportion of the cell’s resources is devoted to translation. The magnitude of this commitment can be appreciated in genetic, biochemical, and cell biological terms. Translation is a sophisticated process requiring extensive biological machinery. One way to gauge the amount of genetic information needed to assemble the protein synthetic machinery is to compile a “parts list” of essential proteins and RNAs. Analyses of the genomes of several microorganisms have converged on similar estimates (Hutchison et al. 1999; Tamas et al. 2002; Kobayashi et al. 2003; Waters et al. 2003). These organisms get by with about 130 genes for components of the translation machinery, including about 90 protein-coding genes (specifying 50–60 ribosomal proteins, about 20 aminoacyl-tRNA synthetases, and 10–15 translation factors) and about 40 genes for ribosomal and transfer RNAs (rRNA and tRNAs). A somewhat larger number of genes are involved in eukaryotes, which have more ribosomal proteins and initiation factors, for example. Discounting genes that are dispensable for growth in the laboratory, it can be calculated that approximately 40% of the genes in a theoretical minimal cellular genome are devoted to the translation apparatus. This heavy...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"42 1","pages":"1-40"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77735388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"2 Structure of the Bacterial Ribosome and Some Implications for Translational Regulation","authors":"H. Noller","doi":"10.1101/087969767.48.41","DOIUrl":"https://doi.org/10.1101/087969767.48.41","url":null,"abstract":"Translational regulation is based on modulation of translational function, most often involving the initiation phase. Not surprisingly, regulation of protein synthesis differs markedly between bacteria and eukarya, reflecting the many differences between their respective mechanisms of initiation. Although the structures of all ribosomes share commonly conserved cores, which are responsible for the main processes of translational elongation, many of the molecular components involved in translational initiation are specific to the different phylogenetic domains. These include the initiation factors, the Shine-Dalgarno sequence, formylation of the methionyl initiator tRNA, the ability to reinitiate on polycistronic mRNAs, and so on. Thus, it is not at all clear how far our knowledge of 70S (prokaryotic) ribosome structure will go toward providing insight into the mechanisms of eukaryotic translational regulation. Nevertheless, this information will help to understand prokaryotic initiation, and at least provide a starting point for interpreting the emerging structures of eukaryotic ribosomes. Most of the steps of protein synthesis appear to be based on RNA, including the many interactions between mRNA, tRNA, and rRNA that occur during the elongation phase. The roles of the proteins, such as the elongation factors and ribosomal proteins, may be to refine underlying RNA-based mechanisms, optimizing the speed and accuracy of translation. Translational initiation, at least in part, is therefore likely to involve modulation of RNA-based processes by proteins such as the initiation factors. We are beginning to understand how some of these processes work, from several decades of biochemical and genetic studies combined with the more recent...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"28 1","pages":"41-58"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87633535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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