Showing papers in "Nature Reviews Molecular Cell Biology in 2004"
TL;DR: The transcription factor HIF (hypoxia-inducible factor) has a central role in oxygen homeostasis in animals ranging from nematode worms to man and is regulated by an unprecedented signalling mechanism that involves post-translational hydroxylation.
Abstract: The transcription factor HIF (hypoxia-inducible factor) has a central role in oxygen homeostasis in animals ranging from nematode worms to man. Recent studies have shown that this factor is regulated by an unprecedented signalling mechanism that involves post-translational hydroxylation. This hydroxylation is catalysed by a set of non-haem, Fe2+-dependent enzymes that belong to the 2-oxoglutarate-dependent-oxygenase superfamily. The absolute requirement of these enzymes for molecular oxygen has provided new insights into the way cells sense oxygen.
1,905 citations
TL;DR: The present understanding of caspase regulation during apoptosis is described and biochemical and structural studies have led to important advances in understanding the underlying molecular mechanisms of cispase regulation.
Abstract: Caspases, which are the executioners of apoptosis, comprise two distinct classes, the initiators and the effectors. Although general structural features are shared between the initiator and the effector caspases, their activation, inhibition and release of inhibition are differentially regulated. Biochemical and structural studies have led to important advances in understanding the underlying molecular mechanisms of caspase regulation. This article reviews these latest advances and describes our present understanding of caspase regulation during apoptosis.
1,877 citations
TL;DR: During progression from tumour growth to metastasis, specific integrin signals enable cancer cells to detach from neighbouring cells, re-orientate their polarity during migration, and survive and proliferate in foreign microenvironments.
Abstract: During progression from tumour growth to metastasis, specific integrin signals enable cancer cells to detach from neighbouring cells, re-orientate their polarity during migration, and survive and proliferate in foreign microenvironments. There is increasing evidence that certain integrins associate with receptor tyrosine kinases (RTKs) to activate signalling pathways that are necessary for tumour invasion and metastasis. The effect of these integrins might be especially important in cancer cells that have activating mutations, or amplifications, of the genes that encode these RTKs.
1,465 citations
TL;DR: The numerous cytokine- and growth-factor-mediated pathways that are involved in regulating liver regeneration are being successfully dissected using molecular and genetic approaches.
Abstract: The unusual regenerative properties of the liver are a logical adaptation by organisms, as the liver is the main detoxifying organ of the body and is likely to be injured by ingested toxins. The numerous cytokine- and growth-factor-mediated pathways that are involved in regulating liver regeneration are being successfully dissected using molecular and genetic approaches. So what is known about this process at present and which questions remain?
1,447 citations
TL;DR: It is proposed that a common mechanism leading to membrane tubulation and/or fission could encompass their many varied functions.
Abstract: Dynamins are large GTPases that belong to a protein superfamily that, in eukaryotic cells, includes classical dynamins, dynamin-like proteins, OPA1, Mx proteins, mitofusins and guanylate-binding proteins/atlastins. They are involved in many processes including budding of transport vesicles, division of organelles, cytokinesis and pathogen resistance. With sequenced genomes from Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, yeast species and Arabidopsis thaliana, we now have a complete picture of the members of the dynamin superfamily from different organisms. Here, we review the superfamily of dynamins and their related proteins, and propose that a common mechanism leading to membrane tubulation and/or fission could encompass their many varied functions.
1,360 citations
TL;DR: The increasing number of sequenced bacterial genomes shows that although the central sensory mechanism seems to be common to all bacteria, there is added complexity in a wide range of species.
Abstract: Bacteria must be able to respond to a changing environment, and one way to respond is to move. The transduction of sensory signals alters the concentration of small phosphorylated response regulators that bind to the rotary flagellar motor and cause switching. This simple pathway has provided a paradigm for sensory systems in general. However, the increasing number of sequenced bacterial genomes shows that although the central sensory mechanism seems to be common to all bacteria, there is added complexity in a wide range of species.
1,293 citations
TL;DR: The acquisition and loss of mRNA-associated proteins accompanies the transition from the pioneer round to subsequent rounds of translation, and from translational competence to substrate for nonsense-mediated mRNA decay.
Abstract: Studies of nonsense-mediated mRNA decay in mammalian cells have proffered unforeseen insights into changes in mRNA–protein interactions throughout the lifetime of an mRNA. Remarkably, mRNA acquires a complex of proteins at each exon–exon junction during pre-mRNA splicing that influences the subsequent steps of mRNA translation and nonsense-mediated mRNA decay. Complex-loaded mRNA is thought to undergo a pioneer round of translation when still bound by cap-binding proteins CBP80 and CBP20 and poly(A)-binding protein 2. The acquisition and loss of mRNA-associated proteins accompanies the transition from the pioneer round to subsequent rounds of translation, and from translational competence to substrate for nonsense-mediated mRNA decay.
1,175 citations
TL;DR: Proteomics is an increasingly powerful and indispensable technology in molecular cell biology as discussed by the authors, which can be used to identify the components of small protein complexes and large organelles, to determine post-translational modifications and in sophisticated functional screens.
Abstract: Proteomics is an increasingly powerful and indispensable technology in molecular cell biology. It can be used to identify the components of small protein complexes and large organelles, to determine post-translational modifications and in sophisticated functional screens. The key — but little understood — technology in mass-spectrometry-based proteomics is peptide sequencing, which we describe and review here in an easily accessible format.
1,173 citations
TL;DR: A report that implicates B-RAF in human cancer has highlighted the importance of all members of this protein kinase family and recent studies have uncovered intriguing new data relating to their complex regulation and biological functions.
Abstract: Since their discovery over 20 years ago, the RAF proteins have been intensely studied. For most of that time, the focus of the field has been the C-RAF isoform and its role as an effector of the RAS proteins. However, a report that implicates B-RAF in human cancer has highlighted the importance of all members of this protein kinase family and recent studies have uncovered intriguing new data relating to their complex regulation and biological functions.
1,170 citations
TL;DR: Junctional structures maintain the integrity of the endothelium and might transfer intracellular signals that regulate contact-induced inhibition of cell growth, apoptosis, gene expression and new vessel formation.
Abstract: Junctional structures maintain the integrity of the endothelium Recent studies have shown that, as well as promoting cell–cell adhesion, junctions might transfer intracellular signals that regulate contact-induced inhibition of cell growth, apoptosis, gene expression and new vessel formation Moreover, modifications of the molecular organization and intracellular signalling of junctional proteins might have complex effects on vascular homeostasis
1,157 citations
TL;DR: The NF-κB/REL family of transcription factors pivotally control the inflammatory and immune responses, as well as other genetic programmes that are central to cell growth and survival.
Abstract: The NF-κB/REL family of transcription factors pivotally control the inflammatory and immune responses, as well as other genetic programmes that are central to cell growth and survival. The cytoplasmic regulation of NF-κB is well characterized and, recently, significant progress has been made in understanding how its nuclear action is regulated. Post-translational modification of the NF-κB subunits as well as histones surrounding the NF-κB target genes has a key role in this regulation. Here, we review the important advances that constitute this new and exciting chapter in NF-κB biology.
TL;DR: In the cytosol of prokaryotic and eukaryotic cells, molecular chaperones of different structural classes form a network of pathways that can handle substrate polypeptides from the point of initial synthesis on ribosomes to the final stages of folding.
Abstract: Cells are faced with the task of folding thousands of different polypeptides into a wide range of conformations. For many proteins, the folding process requires the action of molecular chaperones. In the cytosol of prokaryotic and eukaryotic cells, molecular chaperones of different structural classes form a network of pathways that can handle substrate polypeptides from the point of initial synthesis on ribosomes to the final stages of folding.
TL;DR: A-kinase anchoring proteins are signal-organizing molecules that compartmentalize various enzymes that are regulated by second messengers that provide a molecular framework that orients these enzymes towards selected substrates.
Abstract: Multiprotein signalling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize various enzymes that are regulated by second messengers.
TL;DR: Polo-like kinases are increasingly recognized as key regulators of mitosis, meiosis and cytokinesis and their targeting to different cellular structures through interactions with phosphorylated docking proteins is uncovered.
Abstract: Polo-like kinases (Plks) are increasingly recognized as key regulators of mitosis, meiosis and cytokinesis. In agreement with a broad range of proposed functions during cell division, Plks are subject to complex temporal and spatial control. Recent findings are uncovering the mechanisms of Plk regulation, notably their targeting to different cellular structures through interactions with phosphorylated docking proteins. Moreover, information is emerging on the substrate specificity of Plks and the role of individual substrates in M-phase progression.
TL;DR: A unifying and structurally detailed view of SCF-mediated proteolytic control of cellular processes that has been revealed by recent studies is explored.
Abstract: Ubiquitin ligases are well suited to regulate molecular networks that operate on a post-translational timescale. The F-box family of proteins - which are the substrate-recognition components of the Skp1-Cul1-F-box-protein (SCF) ubiquitin ligase - are important players in many mammalian functions. Here we explore a unifying and structurally detailed view of SCF-mediated proteolytic control of cellular processes that has been revealed by recent studies.
TL;DR: Translational control is widely used to regulate gene expression and is especially relevant in situations where transcription is silent or when local control over protein accumulation is required as mentioned in this paper. But only a few examples of translational regulation are mechanistically understood.
Abstract: Translational control is widely used to regulate gene expression. This mode of regulation is especially relevant in situations where transcription is silent or when local control over protein accumulation is required. Although many examples of translational regulation have been described, only a few are beginning to be mechanistically understood. Instead of providing a comprehensive account of the examples that are known at present, we discuss instructive cases that serve as paradigms for different modes of translational control.
TL;DR: This work states that the discovery of aquaporins has stimulated a reconsideration of membrane water permeability by investigators across a wide range of disciplines and indicates diverse roles in the regulation of water homeostasis.
Abstract: Our understanding of the movement of water through cell membranes has been greatly advanced by the discovery of a family of water-specific, membrane-channel proteins — the aquaporins. These proteins are present in organisms at all levels of life, and their unique permeability characteristics and distribution in numerous tissues indicate diverse roles in the regulation of water homeostasis. The recognition of aquaporins has stimulated a reconsideration of membrane water permeability by investigators across a wide range of disciplines.
TL;DR: New findings indicate that riboswitches are robust genetic elements that are involved in regulating fundamental metabolic processes in many organisms.
Abstract: Riboswitches are complex folded RNA domains that serve as receptors for specific metabolites. These domains are found in the non-coding portions of various mRNAs, where they control gene expression by harnessing allosteric structural changes that are brought about by metabolite binding. New findings indicate that riboswitches are robust genetic elements that are involved in regulating fundamental metabolic processes in many organisms.
TL;DR: The biochemistry of lysosomal storage disorders is summarized and downstream cellular pathways that are potentially affected in these disorders are discussed and that might help to delineate their pathological mechanisms.
Abstract: Lysosomal storage disorders, of which more than 40 are known, are caused by the defective activity of lysosomal proteins, which results in the intra-lysosomal accumulation of undegraded metabolites. Despite years of study of the genetic and molecular bases of lysosomal storage disorders, little is known about the events that lead from this intra-lysosomal accumulation to pathology. Here, we summarize the biochemistry of lysosomal storage disorders. We then discuss downstream cellular pathways that are potentially affected in these disorders and that might help us to delineate their pathological mechanisms.
TL;DR: A growing amount of evidence indicates that polyploid cells also arise during a variety of pathological conditions, and genetic instability in these cells might provide a route to aneuploidy and thereby contribute to the development of cancer.
Abstract: Polyploidy is a frequent phenomenon in the eukaryotic world, but the biological properties of polyploid cells are not well understood. During evolution, polyploidy is thought to be an important mechanism that contributes to speciation. Polyploid, usually non-dividing, cells are formed during development in otherwise diploid organisms. A growing amount of evidence indicates that polyploid cells also arise during a variety of pathological conditions. Genetic instability in these cells might provide a route to aneuploidy and thereby contribute to the development of cancer.
TL;DR: Findings on the emerging mechanisms of activation, the signalling pathways and the spatio-temporal organization of the intra-S-phase DNA-damage checkpoint and its impact on the cell-cycle machinery are integrated and discussed.
Abstract: The precise replication of the genome and the continuous surveillance of its integrity are essential for survival and the avoidance of various diseases. Cells respond to DNA damage by activating a complex network of the so-called checkpoint pathways to delay their cell-cycle progression and repair the defects. In this review we integrate findings on the emerging mechanisms of activation, the signalling pathways and the spatio-temporal organization of the intra-S-phase DNA-damage checkpoint and its impact on the cell-cycle machinery, and discuss its biological significance.
TL;DR: 'Chambered proteases', including the eukaryotic 26S proteasome, use the energy of ATP to drive the unfolding and translocation of a polypeptide substrate into a chamber of sequestered proteolytic active sites.
Abstract: 'Chambered proteases', including the eukaryotic 26S proteasome, use the energy of ATP to drive the unfolding and translocation of a polypeptide substrate into a chamber of sequestered proteolytic active sites These proteases have diverse functions and are found in all three kingdoms of life Understanding chambered proteases requires answers to two questions — how do these remarkable machines select the correct target proteins and how do they bring about the processive degradation of these molecules?
TL;DR: RNA helicases from the DEAD-box family are found in almost all organisms and have important roles in RNA metabolism, associated with many processes ranging from RNA synthesis to RNA degradation.
Abstract: RNA helicases from the DEAD-box family are found in almost all organisms and have important roles in RNA metabolism. They are associated with many processes ranging from RNA synthesis to RNA degradation. DEAD-box proteins use the energy from ATP hydrolysis to rearrange inter- or intra-molecular RNA structures or dissociate RNA–protein complexes. Such dynamic rearrangements are fundamental for many, if not all, steps in the life of an RNA molecule. Recent biochemical, genetic and structural data shed light on how these proteins power the metabolism of RNA within a cell.
TL;DR: Recent work that uncovers some of the mechanisms that cause both membrane invagination within newly forming intermediates and the detachment of these intermediates from early endosomal membranes are discussed.
Abstract: Recent progress has been made in our understanding of the molecular mechanisms that regulate the biogenesis of multivesicular transport intermediates in the degradation pathway that leads to lysosomes. Here, we discuss recent work that uncovers some of the mechanisms that cause both membrane invagination within these newly forming intermediates and the detachment of these intermediates from early endosomal membranes.
TL;DR: First described 15 years ago as a cysteine-rich sequence that was common to a small group of homeodomain transcription factors, the LIM domain is now recognized as a tandem zinc-finger structure that functions as a modular protein-binding interface.
Abstract: First described 15 years ago as a cysteine-rich sequence that was common to a small group of homeodomain transcription factors, the LIM domain is now recognized as a tandem zinc-finger structure that functions as a modular protein-binding interface. LIM domains are present in many proteins that have diverse cellular roles as regulators of gene expression, cytoarchitecture, cell adhesion, cell motility and signal transduction. An emerging theme is that LIM proteins might function as biosensors that mediate communication between the cytosolic and the nuclear compartments.
TL;DR: The concept of metabolite profiling has been around for several decades, but only recent technical innovations have allowed metabolic profiling to be carried out on a large scale with respect to both number of metabolites measured and the number of experiments carried out.
Abstract: The concept of metabolite profiling has been around for several decades, but only recent technical innovations have allowed metabolite profiling to be carried out on a large scale - with respect to both the number of metabolites measured and the number of experiments carried out. As a result, the power of metabolite profiling as a technology platform for diagnostics, and the research areas of gene-function analysis and systems biology, is now beginning to be fully realized.
TL;DR: During random locomotion, human neutrophils and Dictyostelium discoideum amoebae repeatedly extend and retract cytoplasmic processes, and how these molecules become localized in the cell is now becoming clear.
Abstract: During random locomotion, human neutrophils and Dictyostelium discoideum amoebae repeatedly extend and retract cytoplasmic processes. During directed cell migration — chemotaxis — these pseudopodia form predominantly at the leading edge in response to the local accumulation of certain signalling molecules. Concurrent changes in actin and myosin enable the cell to move towards the stimulus. Recent studies are beginning to identify an intricate network of signalling molecules that mediate these processes, and how these molecules become localized in the cell is now becoming clear.
TL;DR: The plasma membrane of many motile cells undergoes highly regulated protrusions and invaginations that support the formation of podosomes, invadopodia and circular dorsal ruffles, which function is to help the cell as it migrates, attaches and invades.
Abstract: The plasma membrane of many motile cells undergoes highly regulated protrusions and invaginations that support the formation of podosomes, invadopodia and circular dorsal ruffles Although they are similar in appearance and in their formation--which is mediated by a highly conserved actin-membrane apparatus--these transient surface membrane distortions are distinct Their function is to help the cell as it migrates, attaches and invades
TL;DR: Heterochromatin maintenance is crucial for the clonal inheritance of cell identity, to ensure the proper segregation of chromosomes and the regulation of gene expression, and recent progress has shed light on the paradoxical properties of heterochromaatin in the nucleus.
Abstract: Heterochromatin maintenance is crucial for the clonal inheritance of cell identity, to ensure the proper segregation of chromosomes and the regulation of gene expression. Although it is architecturally stable, heterochromatin has to be flexible to cope with disrupting events such as replication. Recent progress has shed light on the paradoxical properties of heterochromatin in the nucleus, and highlights the roles of heterochromatin protein-1 and, more unexpectedly, RNA molecules in heterochromatin maintenance.
TL;DR: Structural insights into these complexes are now providing a framework for the exploration not only of energy and electron transfer, but also of the evolutionary forces that shaped the photosynthetic apparatus.
Abstract: Oxygenic photosynthesis is the principal producer of both oxygen and organic matter on earth. The primary step in this process — the conversion of sunlight into chemical energy — is driven by four, multisubunit, membrane-protein complexes that are known as photosystem I, photosystem II, cytochrome b 6 f and F-ATPase. Structural insights into these complexes are now providing a framework for the exploration not only of energy and electron transfer, but also of the evolutionary forces that shaped the photosynthetic apparatus.