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• W2029253886 abstract "Cellular phenotype and function is ultimately determined by the synthesis of proteins derived from a genetic blueprint. Control of gene expression occurs at multiple checkpoints, including the transcription of DNA into RNA and the translation of RNA into protein. Translational control mechanisms are important regulators of cellular phenotype, controlling up to 10% of overall cellular gene expression, yet they remain relatively understudied when compared with transcriptional control mechanisms. Specific regulation of protein synthesis from messenger RNA transcripts allows cells to temporally unlink translation from transcription and provides a mechanism for a more rapid response to environmental signals than if transcription were required. We discuss some of the fundamental concepts of translational control, tools for studying it and its relevance to vascular cells, in particular the endothelium. Cellular phenotype and function is ultimately determined by the synthesis of proteins derived from a genetic blueprint. Control of gene expression occurs at multiple checkpoints, including the transcription of DNA into RNA and the translation of RNA into protein. Translational control mechanisms are important regulators of cellular phenotype, controlling up to 10% of overall cellular gene expression, yet they remain relatively understudied when compared with transcriptional control mechanisms. Specific regulation of protein synthesis from messenger RNA transcripts allows cells to temporally unlink translation from transcription and provides a mechanism for a more rapid response to environmental signals than if transcription were required. We discuss some of the fundamental concepts of translational control, tools for studying it and its relevance to vascular cells, in particular the endothelium. The central dogma of molecular biology states that genetic information flows from DNA to messenger RNA (mRNA; transcription), and from mRNA to protein (translation).1Alberts B. Johnson A. Lewis J. Raff M. Roberts K. Walter P. Molecular biology of the cell. 4th ed. Garland Science, New York2002Google Scholar This model illustrates that genomic DNA does not direct protein synthesis itself, but instead uses mRNA as an intermediary molecule. It is the synthesis of protein from these intermediary mRNA transcripts that ultimately determines cellular phenotype and function. Despite this fact, there is relatively little research into the specific regulation of protein synthesis (as opposed to transcription) in vascular cells.2Day D.A. Tuite M.F. Post-transcriptional gene regulatory mechanisms in eukaryotes: an overview.J Endocrinol. 1998; 157: 361-371Crossref PubMed Scopus (239) Google Scholar The classic view of gene expression describes a series of events triggered by some type of signal that stimulates a cell to transcribe its genetic blueprint, or DNA, into RNA. This transcript is then processed and transported out of the nucleus and into the cytoplasm. Next, the RNA is translated into protein by ribosomes, yielding a protein that ultimately changes the cell’s structure or function to adapt to the initial signal (Fig 1). This simplistic, assembly line view of gene expression suggests that genes are either “on” or “off” as opposed to modulated. Another shortcoming of this model is that it espouses an obligatory temporal relationship in which transcription begets translation rather than a scenario in which many regulatory factors may independently (or perhaps simultaneously) work at multiple checkpoints during gene expression. Clearly, transcription is an essential process: translation cannot occur in the absence of mRNA. Transcription is also the most common site of regulated gene expression, being targeted up to 90% of the time when a cell responds to a stimulus.1Alberts B. Johnson A. Lewis J. Raff M. Roberts K. Walter P. Molecular biology of the cell. 4th ed. Garland Science, New York2002Google Scholar Transcription is time-consuming, however, and requires a significant amount of energy. Translational control is an important means of regulating gene expression because it offers an additional level of control in determining which genes are ultimately expressed in protein form, when, and how much, and because it can occur temporally independent of transcription. There are important instances in which it is to the cell’s advantage to dissociate transcription from translation; this review focuses on some of those instances. Translational control is defined as a change in the efficiency or rate of protein translation of one or more mRNAs resulting in a change in the number of synthesized proteins over time. The benefits of controlling gene expression at the level of translation may be summed up in terms of immediacy, precision, and redundancy.3Sonenberg N. Hershey J.W.B. Mathews M.B. Translational control of gene expression. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2000Google Scholar Immediacy is self-explanatory: if a cell needs to rapidly change its function or phenotype in response to some stimulus, it is much faster to change the translation rate of pre-existing mRNA than it is to synthesize new mRNA before being able to translate proteins from that transcript. Many cells synthesize mRNA and then store it for future use without immediately translating it.4Anderson P. Kedersha N. RNA granules.J Cell Biol. 2006; 172: 803-808Crossref PubMed Scopus (816) Google Scholar These mRNA transcripts are then available for rapid mobilization to the translational apparatus and a rapid change in protein expression given the appropriate stimulus. Such instances are the most obvious example of temporal dissociation of transcription and translation. Translational control offers increased precision of gene expression by regulating small changes in overall protein levels towards the end of a long, complex pathway rather than at the beginning. Take an automotive assembly line, for example. The end product is a car (protein) resulting from a manufacturing process using various raw materials such as steel and rubber (mRNA, amino acids). If the output of the assembly line needs to change by 10%, it makes more sense to exert that control at some point during the assembly process rather than by changing the overall availability of raw materials at the front end. The combination of transcriptional and translational control (redundancy) helps to avoid dysregulated expression of potentially harmful molecules. This is analogous to multiple back-up systems in spacecraft and commercial airlines in which catastrophic malfunctions supposedly cannot occur as a result of a single system failure. Translational control is often imposed on critical gene products such as oncogenes, growth factors, and signaling molecules.5Kozak M. An analysis of vertebrate mRNA sequences: intimations of translational control.J Cell Biol. 1991; 115: 887-903Crossref PubMed Scopus (1441) Google Scholar It is useful to distinguish between global and selective translational control. Global controls govern general processes necessary to translate mRNA and therefore affect translational rates of all classes of mRNA transcripts. Global controls are sensitive to the availability of “raw materials” such as amino acids or energy substrates and are responsible for the overall decrease in protein synthesis that occurs during starvation. Selective controls target features unique to a given mRNA molecule or class of mRNAs possessing that feature. Therefore, a unique subset of mRNA transcripts can be translationally repressed despite an abundance of activated translational components (such as ribosomes), or specialized mRNA transcripts may be increasingly translated despite a condition in which overall protein synthesis is reduced (such as heat shock).6Joshi-Barve S. De Benedetti A. Rhoads R.E. Preferential translation of heat shock mRNAs in HeLa cells deficient in protein synthesis initiation factors eIF-4E and eIF-4 gamma.J Biol Chem. 1992; 267: 21038-21043Abstract Full Text PDF PubMed Google Scholar Synthesizing protein from mRNA transcripts involves three basic steps: (1) initiation, the recruitment and assembly of intact ribosomes at a start codon; (2) elongation, the sequential addition of amino acid residues; and (3) termination, the dissociation of intact ribosomes from the mRNA transcript. In eukaryotic cells, the initiation of translation is a highly regulated, complex process that is the rate-limiting step where regulation of translation most commonly occurs. Translational control is seldom exerted at the elongation or termination steps and is not further described. The molecular machinery required for initiation includes an appropriately processed mRNA molecule, ribosomes, transfer RNA (tRNA) molecules with their associated amino acids, and a group of additional proteins known as eukaryotic initiation factors or eIFs.3Sonenberg N. Hershey J.W.B. Mathews M.B. Translational control of gene expression. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2000Google Scholar After RNA is transcribed from DNA in the nucleus, it is processed by capping the 5′-end with a methylated guanosine, splicing out noncoding intronic sequences, and polyadenylation at the 3′-tail (Fig 2). This mature mRNA transcript is then exported into the cytoplasm where translation occurs. The initiation of translation can occur in several different ways, but the scanning model is thought to be the most common.3Sonenberg N. Hershey J.W.B. Mathews M.B. Translational control of gene expression. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2000Google Scholar In this model, the 40S subunit of a ribosome binds to the capped 5′-terminus of a mature mRNA with the assistance of multiple eIFs (Fig 2). This mode of initiation is thus termed cap-dependent translation. Immediately downstream of the 5′-cap is a section of the mRNA transcript known as the 5′ untranslated region (UTR), which must be scanned by the 40S ribosome subunit before reaching the start codon. The length and secondary structure of the 5′-UTR can profoundly influence translational efficiency by altering access of eIFs to the 5′-cap or by preventing smooth scanning to the start codon.3Sonenberg N. Hershey J.W.B. Mathews M.B. Translational control of gene expression. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2000Google Scholar Messenger RNA transcripts that possess 5′-UTR sequences with an extensive secondary structure frequently code for oncoproteins, growth factors, transcription factors, and proteins that must be tightly regulated for normal cellular function and are an illustration of redundancy.5Kozak M. An analysis of vertebrate mRNA sequences: intimations of translational control.J Cell Biol. 1991; 115: 887-903Crossref PubMed Scopus (1441) Google Scholar There are multiple opportunities for specific control events to occur during the initiation process. Various signal inputs may be required to unmask the 5′-cap so that the 40S ribosome subunit and eIFs can attach and begin scanning. Additional signal inputs may be necessary to assist scanning through highly structured and complicated 5′-UTRs and may involve regulated association or dissociation of various RNA-binding proteins with particular motifs in this region. Translational control can also be exerted through specific interactions between the RNA-binding proteins with the 3′-UTR but are not further discussed here. The types of control that involve regulation of specific events at the mRNA UTRs tend to be selective rather than global. Once the start codon (AUG) is recognized, the bound eIFs are released from the 40S subunit to allow binding of the 60S ribosomal subunit.7Sachs A.B. Sarnow P. Hentze M.W. Starting at the beginning, middle, and end: translation initiation in eukaryotes.Cell. 1997; 89: 831-838Abstract Full Text Full Text PDF PubMed Scopus (584) Google Scholar, 8Kozak M. Shatkin A.J. Identification of features in 5′ terminal fragments from reovirus mRNA which are important for ribosome binding.Cell. 1978; 13: 201-212Abstract Full Text PDF PubMed Scopus (81) Google Scholar A separate eIF is necessary to catalyze the formation of a complete 80S ribosome from the two subunits. At this point, the ribosome is fully assembled on the mRNA transcript at the start codon and translation begins as tRNA molecules supply the appropriate amino acids for protein synthesis. As the ribosome progresses along the transcript, the polypeptide product elongates until the ribosome complex reaches the stop codon towards the end of the 3′-terminus, and translation ceases.9Komar A.A. Hatzoglou M. Internal ribosome entry sites in cellular mRNAs: mystery of their existence.J Biol Chem. 2005; 280: 23425-23428Crossref PubMed Scopus (208) Google Scholar Another model for eukaryotic protein synthesis is based upon the concept of cap-independent translation. This model does not rely on the 5′-mRNA cap with its associated eIFs to recruit ribosomes, as does the scanning model. Instead, internal ribosome entry sites (IRES) exist in which a ribosome can bypass binding to the capped 5′-end of an mRNA and attach directly at a site downstream, within the 5′-UTR (Fig 2).3Sonenberg N. Hershey J.W.B. Mathews M.B. Translational control of gene expression. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2000Google Scholar Viral genomes provided the first evidence for IRES elements because their RNA is not processed and capped as it is in eukaryotes.10Johannes G. Carter M.S. Eisen M.B. Brown P.O. Sarnow P. Identification of eukaryotic mRNAs that are translated at reduced cap binding complex eIF4F concentrations using a cDNA microarray.Proc Natl Acad Sci U S A. 1999; 96: 13118-13123Crossref PubMed Scopus (316) Google Scholar Furthermore, many viruses actually inhibit the host cell’s normal process of cap-dependent translation by disabling key eIFs necessary for cap recognition.11Bushell M. Sarnow P. Hijacking the translation apparatus by RNA viruses.J Cell Biol. 2002; 158: 395-399Crossref PubMed Scopus (137) Google Scholar Viral protein synthesis typically occurs because the host cell ribosomes are diverted from cap-dependent translation of host cell mRNA to cap-independent translation of viral mRNA. It is now appreciated that there are multiple mechanisms for ribosomal recruitment to IRES elements, and there is a growing body of evidence that cells may use cap-independent translation for host protein synthesis at specific times: cellular differentiation,12Bernstein J. Sella O. Le S.Y. Elroy-Stein O. PDGF2/c-sis mRNA leader contains a differentiation-linked internal ribosomal entry site (D-IRES).J Biol Chem. 1997; 272: 9356-9362Crossref PubMed Scopus (153) Google Scholar apoptosis,13Stoneley M. Chappell S.A. Jopling C.L. Dickens M. MacFarlane M. Willis A.E. c-Myc protein synthesis is initiated from the internal ribosome entry segment during apoptosis.Mol Cell Biol. 2000; 20: 1162-1169Crossref PubMed Scopus (191) Google Scholar and in certain pathologic conditions such as Charcot-Marie-Tooth disease and multiple myeloma.14Hellen C.U. Sarnow P. Internal ribosome entry sites in eukaryotic mRNA molecules.Genes Dev. 2001; 15 (1593-12)Crossref PubMed Scopus (786) Google Scholar, 15Chappell S.A. LeQuesne J.P. Paulin F.E. deSchoolmeester M.L. Stoneley M. Soutar R.L. et al.A mutation in the c-myc-IRES leads to enhanced internal ribosome entry in multiple myeloma: a novel mechanism of oncogene de-regulation.Oncogene. 2000; 19: 4437-4440Crossref PubMed Scopus (118) Google Scholar, 16Hudder A. Werner R. Analysis of a Charcot-Marie-Tooth disease mutation reveals an essential internal ribosome entry site element in the connexin-32 gene.J Biol Chem. 2000; 275: 34586-34591Crossref PubMed Scopus (83) Google Scholar Regardless of the manner in which translation is initiated, the ribosome is a fundamental component required for protein synthesis. A single, functional ribosome physically occupies only a short stretch of mRNA, allowing multiple ribosomes to attach to the same transcript to more efficiently produce the protein being synthesized. Transcripts with multiple ribosomes attached are termed polyribosomes, or polysomes, and transcripts associated with a solitary ribosome are termed monosomes. Recall that the formal definition of translational control involves a change in the efficiency of mRNA translation or a change in the number of completed proteins per unit of time. Direct measurement of this parameter is very difficult, so a more convenient surrogate measure is typically used to indirectly assess translational efficiency. This surrogate measurement is the number of ribosomes attached to a given mRNA transcript. Because initiation is usually the rate-limiting step in translation, the number of ribosomes attached to a given mRNA molecule also reflects the efficiency of initiation, which is also the most common site of control. Thus, measurement of the number of ribosomes attached to various mRNA molecules under various conditions provides important clues to the regulatory events governing translation in those particular situations. Specifically, mRNA transcripts associated with polysomes are presumed to be efficiently translated, whereas mRNA transcripts associated with monosomes (or not present in the ribosomal preparation at all) are inefficiently translated. The technique of ribosome profiling (Fig 3) is used to assess how many ribosomes are attached to mRNA molecules. The most important concept in the experimental study of translational regulation is the idea that signal-dependent or condition-dependent redistribution of mRNA between the polysome or monosome fractions is prima facie evidence of translational control. A widely used parameter to reflect translational efficiency for a given mRNA is the “translation state,” which is simply the ratio of the amount of mRNA in the polysome fraction divided by the amount of mRNA in the monosome fraction. Messenger RNA species with translation state >1 are efficiently translated and those with a translation state <1 are not. A significant change in measured translation state between different experimental conditions is also evidence of translational control. Initially, methods for direct analysis of protein expression (or proteome analysis) were cumbersome, insensitive, and limited in their ability to assess large numbers of genes for translational activity.17Garrels J.I. McLaughlin C.S. Warner J.R. Futcher B. Latter G.I. Kobayashi R. et al.Proteome studies of Saccharomyces cerevisiae: identification and characterization of abundant proteins.Electrophoresis. 1997; 18: 1347-1360Crossref PubMed Scopus (115) Google Scholar Classically, translational control was recognized in experiments when a given condition could induce changes in protein levels without corresponding changes in mRNA levels. A high-throughput method for simultaneously monitoring the translational state of large numbers of individual mRNA species was first described in 1999 by Zong et al.18Zong Q. Schummer M. Hood L. Morris D.R. Messenger RNA translation state: the second dimension of high-throughput expression screening.Proc Natl Acad Sci U S A. 1999; 96: 10632-10636Crossref PubMed Scopus (155) Google Scholar This technique, known as translation state array analysis (TSAA; Fig 4), combines microarray technology with ribosomal profiling to determine the translation state of thousands of mRNA species simultaneously. Poorly translated mRNA transcripts associated with monosomes are separated from efficiently translated mRNA transcripts in polysomes by ribosomal profiling (Fig 3). In this instance, all fractions containing two or more ribosomes are pooled to form the polysome fraction. After isolation of RNA from monosome or polysome fractions, fluorescent-labeled complimentary DNA (cDNA) copies of the mRNA transcripts are synthesized and used to interrogate DNA arrays on which thousands of known gene sequences are bound. Because monosome cDNA is labeled with a different fluorophore than polysome cDNA, competitive hybridization yields a measure of the translation state for each gene on the array (Fig 4). If separate arrays are used for control and test conditions, the simultaneous measurement of experimentally induced changes in translation state for thousands of genes is possible. The change in translation state for a given experiment can be expressed by the translation index, which is simply the ratio of the measured translation state under the experimental conditions divided by the measured control translation state. A translation index >1 implies translational upregulation since the conditions of the experiment have redistributed mRNA to the polysome relative to the control situation. A translation index <1 implies translational repression since the experiment has resulted in a redistribution of mRNA out of the polysome and into the monosome. A key attribute of TSAA is that it can recognize translational control even when there is concomitant transcriptional control, because the translation state and the translation index only reflect the proportions (not total amounts) of mRNA in the two fractions. If a third array chip is added to a given experiment, transcriptional control can also be directly assessed by traditional microarray methods. Total RNA is isolated from cells in both the treatment and control conditions and fluorescently labeled cDNA probes from both conditions are used to competitively hybridize with the third chip. Thus, with three arrays, it is possible to simultaneously assess both transcriptional and translational changes. Based on the results of TSAA experiments, we have categorized nine different patterns in which gene expression is potentially regulated in response to a given stimulus in terms of transcriptional and translational indices (Table).TableTypes of transcriptional and translational control as predicted by translation state array analysisCategoryDescriptionTranslationTranscriptionPositive redistributionShift of mRNA from monosome to polysome; no change in total mRNA abundanceIncreasedStaticNegative redistributionShift of mRNA from polysome to monosome; no change in total mRNA abundanceDecreasedStaticCo-ordinate activationShift of mRNA from monosome to polysome out of proportion to increased total mRNA abundanceIncreasedIncreasedCo-ordinate repressionShift of mRNA from polysome to monosome out of proportion to decreased total mRNA abundanceDecreasedDecreasedParadoxical activationShift of mRNA from monosome to polysome despite a reduction in overall mRNA abundanceIncreasedDecreasedParadoxical repressionShift of mRNA from polysome to monosome despite a reduction in overall mRNA abundanceDecreasedIncreasedObligatory upregulationIncreased mRNA in both monosome and polysome paralleling overall increase in mRNA abundanceStaticIncreasedObligatory downregulationDecreased mRNA in both monosme and polysome paralleling overall reduction in mRNA abundanceStaticDecreasedNo regulationNo change in mRNA in monosomes or polysomes; no overall change in mRNA abundanceStaticStaticmRNA, Messenger RNA. Open table in a new tab mRNA, Messenger RNA. Data derived from TSAA experiments should be validated using molecular biology techniques such as quantitative polymerase chain reaction (PCR). In addition, TSAA-derived data do not give any information about the function of the gene or genes in question. Traditional cell biologic studies are still necessary to determine the importance of the observed changes in translation (and transcription). Vascular endothelial cells prominently use translational control mechanisms. Despite early beliefs that these cells were merely bystanders lining the inside of the blood vessels, it is now clear that they play a dynamic role in determining the ultimate biologic behavior of the vessel wall.19Cines D.B. Pollak E.S. Buck C.A. Loscalzo J. Zimmerman G.A. McEver R.P. et al.Endothelial cells in physiology and in the pathophysiology of vascular disorders.Blood. 1998; 91: 3527-3561PubMed Google Scholar Endothelial cells respond to signals from the environment with rapid functional and phenotypic changes. These alterations in endothelial phenotype are inducible by a variety of agonists that act at various receptors. Unregulated endothelial activation is found in numerous pathologic conditions, including sepsis, inflammation, and ischemia-reperfusion injury.20Fink M.P. Abraham E. Vincent J.L. Kochanek P.M. Textbook of critical care. 5th ed. Elsevier Saunders, Philadelphia2005Google Scholar With the explosion of endovascular interventions, there is also an increasing amount of direct mechanical trauma to endothelial cells injured by balloon catheters, stents, and endografts. The rapidity with which endothelial cells can alter their phenotype in response to these environmental stressors listed supports the notion that translational control mechanisms play a significant role in regulating their function. The response of endothelial cells to external stimuli may occur within a broad timeframe, ranging from seconds to days. Second-to-second responses generally involve phosphorylation or dephosphorylation modifications of proteins. Transcriptional control mechanisms may require many hours or even days. Translational control responses tend to occur in a matter of minutes to hours, providing the cell with the opportunity to mount a phenotypic response to an environmental challenge in an intermediate time frame (immediacy). Fluid shear stress is a particularly relevant environmental stimulus to endothelial cells with well-known effects on endothelial phosphorylation events and transcription.21Boo Y.C. Shear stress stimulates phosphorylation of protein kinase A substrate proteins including endothelial nitric oxide synthase in endothelial cells.Exp Mol Med. 2006; 38;: 453Crossref PubMed Google Scholar Our group has shown that fluid shear stress also influences translational activity in vascular endothelium.22Davies P.F. Flow-mediated endothelial mechanotransduction.Physiol Rev. 1995; 75: 519-560Crossref PubMed Scopus (2246) Google Scholar, 23Kraiss L.W. Weyrich A.S. Alto N.M. Dixon D.A. Ennis T.M. Modur V. et al.Fluid flow activates a regulator of translation, p70/p85 S6 kinase, in human endothelial cells.Am J Physiol Heart Circ Physiol. 2000; 278: H1537-H1544PubMed Google Scholar The mammalian target of rapamycin (mTOR) pathway is a ubiquitous signaling system that regulates translation in many cell types.24Gingras A.C. Raught B. Sonenberg N. Regulation of translation initiation by FRAP/mTOR.Genes Dev. 2001; 15: 807-826Crossref PubMed Scopus (1149) Google Scholar The mTOR is a protein kinase that directs phosphorylation of related protein kinases including S6K1 (S6 kinase 1, previously known as P70/P85 S6 kinase).25Hay N. Sonenberg N. Upstream and downstream of mTOR.Genes Dev. 2004; 18: 1926-1945Crossref PubMed Scopus (3298) Google Scholar Activation of the mTOR pathway is crucial to the initiation of protein synthesis in many circumstances. Rapamycin (or sirolimus) is a peptide isolated from the bacteria Streptomyces hygroscopicus. It is an important adjunct in the study of translational control because it directly inhibits mTOR activity. Rapamycin also has clinical applications as an immunosuppressant and an inhibitor of cell growth when eluted from specialized vascular stents. Fluid flow activates the mTOR pathway in endothelial cell and results in activation of S6K1, which facilitates 40S ribosomal recruitment to specific mRNAs (initiation).23Kraiss L.W. Weyrich A.S. Alto N.M. Dixon D.A. Ennis T.M. Modur V. et al.Fluid flow activates a regulator of translation, p70/p85 S6 kinase, in human endothelial cells.Am J Physiol Heart Circ Physiol. 2000; 278: H1537-H1544PubMed Google Scholar, 26Jefferies H.B. Fumagalli S. Dennis P.B. Reinhard C. Pearson R.B. Thomas G. Rapamycin suppresses 5′ TOP mRNA translation through inhibition of p70s6k.Embo J. 1997; 16: 3693-3704Crossref PubMed Scopus (798) Google Scholar In addition, fluid flow induces a rapid increase in the synthesis of Bcl-3, a transcription factor that is a member of the nuclear factor-κ B (NF-κB) family of transcription regulators. A key finding in these studies was that rapamycin effectively blocked both the activation of S6K1 and the synthesis of Bcl-3, but transcriptional inhibition with actinomycin did not.23Kraiss L.W. Weyrich A.S. Alto N.M. Dixon D.A. Ennis T.M. Modur V. et al.Fluid flow activates a regulator of translation, p70/p85 S6 kinase, in human endothelial cells.Am J Physiol Heart Circ Physiol. 2000; 278: H1537-H1544PubMed Google Scholar Additional studies have demonstrated that the translation of E-selectin is modulated by shear stress.27Kraiss L.W. Alto N.M. Dixon D.A. McIntyre T.M. Weyrich A.S. Zimmerman G.A. Fluid flow regulates E-selectin protein levels in human endothelial cells by inhibiting translation.J Vasc Surg. 2003; 37: 161-168Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar E-selectin, a cell surface molecule inducibly expressed by endothelial cells, is critical in leukocyte adhesion and overall endothelial cell activation. Expression of E-selectin protein by endothelial cells was induced using the traditional inflammatory agonist tumor necrosis factor-α (TNF-α). Exposure to fluid flow attenuated the expression of E-selectin in the presence of TNF- α when compared with cells not exposed to fluid flow. Fluid flow did not reduce overall E-selectin mRNA levels but did reduce the amount of E-selectin mRNA associated with polysomes, implying the existence of a regulatory step that specifically regulated access of the mRNA to the protein synthesis machinery, a form of translational control. Of interest was that neither rapamycin nor nitric oxide synthase inhibitors eliminated the modulatory effect of flow on E-selectin expression.23Kraiss L.W. Weyrich A.S. Alto N.M. Dixon D.A. Ennis T.M. Modur V. et al.Fluid flow activates a regulator of translation, p70/p85 S6 kinase, in human endothelial cells.Am J Physiol Heart Circ Physiol. 2000; 278: H1537-H1544PubMed Google Scholar, 27Kraiss L.W. Alto N.M. Dixon D.A. McIntyre T.M. Weyrich A.S. Zimmerman G.A. Fluid flow regulates E-selectin protein levels in human endothelial cells by inhibiting translation.J Vasc Surg. 2003; 37: 161-168Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar This series of discoveries illustrates the concept that endothelial cells can rapidly alter protein synthesis by discrete translational control mechanisms independently of transcription. These observations also emphasize the importance of translational control in endothelial cells because of the existence of multiple regulatory pathways, some of which are independent of the mTOR system and the classic flow-dependent nitric oxide–signaling pathway. Recently, translational control mechanisms have been identified in other important cellular components in the vascular system. Platelets, leukocytes, and vascular smooth muscle cells all exhibit some degree of translational control.28Yost C.C. Denis M.M. Lindemann S. Rubner F.J. Marathe G.K. Buerke M. et al.Activated polymorphonuclear leukocytes rapidly synthesize retinoic acid receptor-alpha: a mechanism for translational control of transcriptional events.J Exp Med. 2004; 200: 671-680Crossref PubMed Scopus (45) Google Scholar, 29Braun-Dullaeus R.C. Mann M.J. Seay U. Zhang L. von Der Leyen H.E. Morris R.E. et al.Cell cycle protein expression in vascular smooth muscle cells in vitro and in vivo is regulated through phosphatidylinositol 3-kinase and mammalian target of rapamycin.Arterioscler Thromb Vasc Biol. 2001; 21: 1152-1158Crossref PubMed Scopus (130) Google Scholar, 30Weyrich A.S. Dixon D.A. Pabla R. Elstad M.R. McIntyre T.M. Prescott S.M. et al.Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets.Proc Natl Acad Sci U S A. 1998; 95: 5556-5561Crossref PubMed Scopus (231) Google Scholar Platelets are intriguing cells for the study of translational control because they are anucleate and lack DNA. Despite this fact, thrombin stimulates platelet synthesis of a number of proteins from pre-existing mRNA stores derived from the parent megakaryocyte.31Weyrich A.S. Lindemann S. Tolley N.D. Kraiss L.W. Dixon D.A. Mahoney T.M. et al.Change in protein phenotype without a nucleus: translational control in platelets.Semin Thromb Hemost. 2004; 30: 491-498Crossref PubMed Scopus (100) Google Scholar In particular, platelet expression of the transcription factor Bcl-3 is induced by thrombin activation. This was a confusing finding initially because platelets would appear to have no use for a transcription factor. Subsequent studies revealed Bcl-3 to have activities apart from transcriptional regulation, including participation in platelet-mediated clot retraction.32Weyrich A.S. Denis M.M. Schwertz H. Tolley N.D. Foulks J. Spencer E. et al.mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets.Blood. 2007; 109: 1975-1983Crossref PubMed Scopus (114) Google Scholar Expression of Bcl-3 protein is diminished by the translational inhibitor rapamycin, demonstrating that platelets regulate protein synthesis through signal-dependent activation of translation despite a lack of transcriptional activity. Regulation of gene expression is a complex process, and although a great deal of work has been done on transcriptional regulation in vascular biology, there are many other factors that determine whether or not a gene ultimately produces a functional protein that can alter cellular phenotype and function. Translational control mechanisms represent one manner in which cells can regulate gene expression, and although research efforts have increased in this field, it remains vastly understudied. Translation is a complex process involving interactions between outside signals, cellular machinery, enzymes, and genetic material. Manipulation of these interactions can drastically alter cellular function, even in the absence of transcriptional changes. With the realization that translational control is separately targeted by extracellular signals, the classic notion of sequential control of gene expression shown in Fig 1 has been refined to reflect the complex and simultaneous nature of parallel signal input for both transcriptional and translational regulation shown in Fig 5." @default.
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