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Anne E. Willis - One of the best experts on this subject based on the ideXlab platform.
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Control of Translation in the cold: implications for therapeutic hypothermia
Biochemical Society Transactions, 2015Co-Authors: John R. P. Knight, Anne E. WillisAbstract:Controlled whole-body cooling has been used since the 1950s to protect the brain from injury where cerebral blood flow is reduced. Therapeutic hypothermia has been used successfully during heart surgery, following cardiac arrest and with varied success in other instances of reduced blood flow to the brain. However, why reduced temperature is beneficial is largely unknown. Here we review the use of therapeutic hypothermia with a view to understanding the underlying biology contributing to the phenomenon. Interestingly, the benefits of cooling have recently been extended to treatment of chronic neurodegenerative diseases in two mouse models. Concurrently studies have demonstrated the importance of the regulation of protein synthesis, Translation, to the cooling response, which is also emerging as a targetable process in neurodegeneration. Through these studies the potential importance of the rewarming process following cooling is also beginning to emerge. Altogether, these lines of research present new opportunities to manipulate cooling pathways for therapeutic gain.
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RNA binding protein/RNA element interactions and the Control of Translation.
Current Protein & Peptide Science, 2012Co-Authors: Xavier Pichon, Lindsay A. Wilson, Mark Stoneley, Amandine Bastide, Helen A. King, Joanna Somers, Anne E. WillisAbstract:A growing body of work demonstrates the importance of post-transcriptional Control, in particular Translation initiation, in the overall regulation of gene expression. Here we focus on the contribution of regulatory elements within the 5’ and 3’ untranslated regions of mRNA to gene expression in eukaryotic cells including terminal oligopyrimidine tracts, internal ribosome entry segments, upstream open reading frames and cytoplasmic polyadenylation elements. These mRNA regulatory elements may adopt complex secondary structures and/or contain sequence motifs that allow their interaction with a variety of regulatory proteins, RNAs and RNA binding proteins, particularly hnRNPs. The resulting interactions are context-sensitive, and provide cells with a sensitive and fast response to cellular signals such as hormone exposure or cytotoxic stress. Importantly, an increasing number of diseases have been identified, particularly cancers and those associated with neurodegeneration, which originate either from mutation of these regulatory motifs, or from deregulation of their cognate binding partners.
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rna binding protein rna element interactions and the Control of Translation
Current Protein & Peptide Science, 2012Co-Authors: Xavier Pichon, Lindsay A. Wilson, Mark Stoneley, Amandine Bastide, Helen A. King, Joanna Somers, Anne E. WillisAbstract:A growing body of work demonstrates the importance of post-transcriptional Control, in particular Translation initiation, in the overall regulation of gene expression. Here we focus on the contribution of regulatory elements within the 5’ and 3’ untranslated regions of mRNA to gene expression in eukaryotic cells including terminal oligopyrimidine tracts, internal ribosome entry segments, upstream open reading frames and cytoplasmic polyadenylation elements. These mRNA regulatory elements may adopt complex secondary structures and/or contain sequence motifs that allow their interaction with a variety of regulatory proteins, RNAs and RNA binding proteins, particularly hnRNPs. The resulting interactions are context-sensitive, and provide cells with a sensitive and fast response to cellular signals such as hormone exposure or cytotoxic stress. Importantly, an increasing number of diseases have been identified, particularly cancers and those associated with neurodegeneration, which originate either from mutation of these regulatory motifs, or from deregulation of their cognate binding partners.
Nahum Sonenberg - One of the best experts on this subject based on the ideXlab platform.
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Control of Translation and mirna dependent repression by a novel poly a binding protein hnrnp q
PLOS Biology, 2013Co-Authors: Yuri V Svitkin, Akiko Yanagiya, Alexey Karetnikov, Tommy Alain, Marc R Fabian, Arkady Khoutorsky, Sandra Perreault, Ivan Topisirovic, Nahum SonenbergAbstract:Translation Control often operates via remodeling of messenger ribonucleoprotein particles. The poly(A) binding protein (PABP) simultaneously interacts with the 3′ poly(A) tail of the mRNA and the eukaryotic Translation initiation factor 4G (eIF4G) to stimulate Translation. PABP also promotes miRNA-dependent deadenylation and Translational repression of target mRNAs. We demonstrate that isoform 2 of the mouse heterogeneous nuclear protein Q (hnRNP-Q2/SYNCRIP) binds poly(A) by default when PABP binding is inhibited. In addition, hnRNP-Q2 competes with PABP for binding to poly(A) in vitro. Depleting hnRNP-Q2 from Translation extracts stimulates cap-dependent and IRES-mediated Translation that is dependent on the PABP/poly(A) complex. Adding recombinant hnRNP-Q2 to the extracts inhibited Translation in a poly(A) tail-dependent manner. The displacement of PABP from the poly(A) tail by hnRNP-Q2 impaired the association of eIF4E with the 5′ m7G cap structure of mRNA, resulting in the inhibition of 48S and 80S ribosome initiation complex formation. In mouse fibroblasts, silencing of hnRNP-Q2 stimulated Translation. In addition, hnRNP-Q2 impeded let-7a miRNA-mediated deadenylation and repression of target mRNAs, which require PABP. Thus, by competing with PABP, hnRNP-Q2 plays important roles in the regulation of global Translation and miRNA-mediated repression of specific mRNAs.
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eif4e the mrna cap binding protein from basic discovery to Translational research
Biochemistry and Cell Biology, 2008Co-Authors: Nahum SonenbergAbstract:Translational Control is an important strategy by which eukaryotic cells regulate gene expression. Translation is the last step in the flow of genetic information, and regulation at this level allows an immediate and rapid response to changes under physiological conditions. Because the processes of mRNA biogenesis, including transcription, splicing, and export to the cytoplasm, are time consuming, the use of pre-existing mRNAs via the Control of Translation is advantageous in many circumstances. A prime target of Translational Control is the initiation factor eIF4E, which recognizes the m7GpppN cap structure present at the 5' end of all nuclear transcribed eukaryotic mRNAs. In this article I describe the discovery of eIF4E, its mechanism of action in Translation initiation, and its role in the Control of cancer and innate immunity.
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Control of Translation by the Target of Rapamycin Proteins
Signaling Pathways for Translation, 2001Co-Authors: Anne-claude Gingras, Brian Raught, Nahum SonenbergAbstract:Regulation of Translation rates, the frequency with which a given mRNA is translated, plays an important role in the Control of cell growth and differentiation. Translational Control is exerted in most instances at the initiation phase, a rate-limiting step during which the ribosome is recruited to mRNA. Initiation is a complex process mediated by many Translation initiation factors (at least 30 polypeptides), and the regulation of Translation initiation factor activity involves modulation of gene expression, binding to other factors or repressors, proteolytic cleavage and changes in phosphorylation state. It has been known for some time that the phosphorylation state of various Translation factors/inhibitors (and other proteins required for Translation, such as ribosomal proteins) is modulated in response to hormonal/mitogenic signals and environmental or nutritional stresses, but the identity of the signaling pathways involved in Translational regulation are only beginning to emerge. In this review, we describe a signaling module involved in Translational Control both in yeast and in mammalian cells, the TOR (or FRAP/mTOR) signaling pathway. In mammals, this pathway regulates the activity of several Translation factors (eIF4B and eIF4GI), Translation inhibitors (the 4E-BPs), and the ribosomal S6 kinases (S6K1 and 2). In yeast, inhibition of Tor activity leads to polysomal disaggregation and G 1 cell cycle arrest.
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Translational homeostasis eukaryotic Translation initiation factor 4e Control of 4e binding protein 1 and p70 s6 kinase activities
Molecular and Cellular Biology, 1999Co-Authors: Kianoush Khaleghpour, Anne-claude Gingras, Stephane Pyronnet, Nahum SonenbergAbstract:Eukaryotic Translation initiation factor 4E (eIF4E) is the mRNA 5′ cap binding protein, which plays an important role in the Control of Translation. The activity of eIF4E is regulated by a family of repressor proteins, the 4E-binding proteins (4E-BPs), whose binding to eIF4E is determined by their phosphorylation state. When hyperphosphorylated, 4E-BPs do not bind to eIF4E. Phosphorylation of the 4E-BPs is effected by the phosphatidylinositol (PI) 3-kinase signal transduction pathway and is inhibited by rapamycin through its binding to FRAP/mTOR (FK506 binding protein–rapamycin-associated protein or mammalian target of rapamycin). Phosphorylation of 4E-BPs can also be induced by protein synthesis inhibitors. These observations led to the proposal that FRAP/mTOR functions as a “sensor” of the Translational apparatus (E. J. Brown and S. L. Schreiber, Cell 86:517–520, 1996). To test this model, we have employed the tetracycline-inducible system to increase eIF4E expression. Removal of tetracycline induced eIF4E expression up to fivefold over endogenous levels. Strikingly, upon induction of eIF4E, 4E-BP1 became dephosphorylated and the extent of dephosphorylation was proportional to the expression level of eIF4E. Dephosphorylation of p70S6k also occurred upon eIF4E induction. In contrast, the phosphorylation of Akt, an upstream effector of both p70S6k and 4E-BP phosphorylation, was not affected by eIF4E induction. We conclude that eIF4E engenders a negative feedback loop that targets a component of the PI 3-kinase signalling pathway which lies downstream of PI 3-kinase.
Roy Parker - One of the best experts on this subject based on the ideXlab platform.
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P-Bodies and Stress Granules: Possible Roles in the Control of Translation and mRNA Degradation
Cold Spring Harbor Perspectives in Biology, 2012Co-Authors: Carolyn J. Decker, Roy ParkerAbstract:The Control of Translation and mRNA degradation is important in the regulation of eukaryotic gene expression. In general, Translation and steps in the major pathway of mRNA decay are in competition with each other. mRNAs that are not engaged in Translation can aggregate into cytoplasmic mRNP granules referred to as processing bodies (P-bodies) and stress granules, which are related to mRNP particles that Control Translation in early development and neurons. Analyses of P-bodies and stress granules suggest a dynamic process, referred to as the mRNA Cycle, wherein mRNPs can move between polysomes, P-bodies and stress granules although the functional roles of mRNP assembly into higher order structures remain poorly understood. In this article, we review what is known about the coupling of Translation and mRNA degradation, the properties of P-bodies and stress granules, and how assembly of mRNPs into larger structures might influence cellular function.
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edc3p and a glutamine asparagine rich domain of lsm4p function in processing body assembly in saccharomyces cerevisiae
Journal of Cell Biology, 2007Co-Authors: Carolyn J. Decker, Daniela Teixeira, Roy ParkerAbstract:Processing bodies (P-bodies) are cytoplasmic RNA granules that contain Translationally repressed messenger ribonucleoproteins (mRNPs) and messenger RNA (mRNA) decay factors. The physical interactions that form the individual mRNPs within P-bodies and how those mRNPs assemble into larger P-bodies are unresolved. We identify direct protein interactions that could contribute to the formation of an mRNP complex that consists of core P-body components. Additionally, we demonstrate that the formation of P-bodies that are visible by light microscopy occurs either through Edc3p, which acts as a scaffold and cross-bridging protein, or via the “prionlike” domain in Lsm4p. Analysis of cells defective in P-body formation indicates that the concentration of Translationally repressed mRNPs and decay factors into microscopically visible P-bodies is not necessary for basal Control of Translation repression and mRNA decay. These results suggest a stepwise model for P-body assembly with the initial formation of a core mRNA–protein complex that then aggregates through multiple specific mechanisms.
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Control of Translation and mRNA degradation by miRNAs and siRNAs
Genes and Development, 2006Co-Authors: Marco Antonio Valencia-sanchez, Jidong Liu, Gregory J Hannon, Roy ParkerAbstract:The Control of Translation and mRNA degradation is an important part of the regulation of gene expression. It is now clear that small RNA molecules are common and effective modulators of gene expression in many eukaryotic cells. These small RNAs that Control gene expression can be either endogenous or exogenous micro RNAs (miRNAs) and short interfering RNAs (siRNAs) and can affect mRNA degradation and Translation, as well as chromatin structure, thereby having impacts on transcription rates. In this review, we discuss possible mechanisms by which miRNAs Control Translation and mRNA degradation. An emerging theme is that miRNAs, and siRNAs to some extent, target mRNAs to the general eukaryotic machinery for mRNA degradation and Translation Control.
Xavier Pichon - One of the best experts on this subject based on the ideXlab platform.
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RNA binding protein/RNA element interactions and the Control of Translation.
Current Protein & Peptide Science, 2012Co-Authors: Xavier Pichon, Lindsay A. Wilson, Mark Stoneley, Amandine Bastide, Helen A. King, Joanna Somers, Anne E. WillisAbstract:A growing body of work demonstrates the importance of post-transcriptional Control, in particular Translation initiation, in the overall regulation of gene expression. Here we focus on the contribution of regulatory elements within the 5’ and 3’ untranslated regions of mRNA to gene expression in eukaryotic cells including terminal oligopyrimidine tracts, internal ribosome entry segments, upstream open reading frames and cytoplasmic polyadenylation elements. These mRNA regulatory elements may adopt complex secondary structures and/or contain sequence motifs that allow their interaction with a variety of regulatory proteins, RNAs and RNA binding proteins, particularly hnRNPs. The resulting interactions are context-sensitive, and provide cells with a sensitive and fast response to cellular signals such as hormone exposure or cytotoxic stress. Importantly, an increasing number of diseases have been identified, particularly cancers and those associated with neurodegeneration, which originate either from mutation of these regulatory motifs, or from deregulation of their cognate binding partners.
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rna binding protein rna element interactions and the Control of Translation
Current Protein & Peptide Science, 2012Co-Authors: Xavier Pichon, Lindsay A. Wilson, Mark Stoneley, Amandine Bastide, Helen A. King, Joanna Somers, Anne E. WillisAbstract:A growing body of work demonstrates the importance of post-transcriptional Control, in particular Translation initiation, in the overall regulation of gene expression. Here we focus on the contribution of regulatory elements within the 5’ and 3’ untranslated regions of mRNA to gene expression in eukaryotic cells including terminal oligopyrimidine tracts, internal ribosome entry segments, upstream open reading frames and cytoplasmic polyadenylation elements. These mRNA regulatory elements may adopt complex secondary structures and/or contain sequence motifs that allow their interaction with a variety of regulatory proteins, RNAs and RNA binding proteins, particularly hnRNPs. The resulting interactions are context-sensitive, and provide cells with a sensitive and fast response to cellular signals such as hormone exposure or cytotoxic stress. Importantly, an increasing number of diseases have been identified, particularly cancers and those associated with neurodegeneration, which originate either from mutation of these regulatory motifs, or from deregulation of their cognate binding partners.
Carine Barreau - One of the best experts on this subject based on the ideXlab platform.
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mammalian celf bruno like rna binding proteins molecular characteristics and biological functions
Biochimie, 2006Co-Authors: Carine Barreau, Luc Paillard, Agnes Mereau, Beverley H OsborneAbstract:In mammals, the CELF/Bruno-like family of RNA-binding proteins contains six members. The founder members of the family are the CUG-BP1 (CELF1) and ETR-3 (CELF2) proteins. Four other members have been identified mainly by sequence similarity. The founder members were cloned or identified in a number of laboratories which has lead to a profusion of names and two separate naming systems. In addition, different members of the CELF/Bruno-like protein family have been shown to be implicated in two major post-transcriptional regulatory processes, namely the alternative splicing and the Control of Translation and stability of target mRNAs. Several studies have indicated a certain functional redundancy between the CELF proteins in fulfilling these functions. The multiplicity of gene names and the eventual functional redundancy is a source of potential confusion in published work. We present here a synthetic picture of the present situation and, where possible, models are proposed that can account for the data obtained in the various laboratories with different biological models. Furthermore, we have highlighted some important questions that still need to be resolved.
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Mammalian CELF/Bruno-like RNA-binding proteins: molecular characteristics and biological functions.
Biochimie, 2006Co-Authors: Carine Barreau, Luc Paillard, Agnes Mereau, Howard Beverley OsborneAbstract:In mammals, the CELF/Bruno-like family of RNA-binding proteins contains six members. The founder members of the family are the CUG-BP1 (CELF1) and ETR-3 (CELF2) proteins. Four other members have been identified mainly by sequence similarity. The founder members were cloned or identified in a number of laboratories which has lead to a profusion of names and two separate naming systems. In addition, different members of the CELF/Bruno-like protein family have been shown to be implicated in two major post-transcriptional regulatory processes, namely the alternative splicing and the Control of Translation and stability of target mRNAs. Several studies have indicated a certain functional redundancy between the CELF proteins in fulfilling these functions. The multiplicity of gene names and the eventual functional redundancy is a source of potential confusion in published work. We present here a synthetic picture of the present situation and, where possible, models are proposed that can account for the data obtained in the various laboratories with different biological models. Furthermore, we have highlighted some important questions that still need to be resolved.