Showing papers in "EMBO Reports in 2006"

The gut flora as a forgotten organ

Abstract: The intestinal microflora is a positive health asset that crucially influences the normal structural and functional development of the mucosal immune system. Mucosal immune responses to resident intestinal microflora require precise control and an immunosensory capacity for distinguishing commensal from pathogenic bacteria. In genetically susceptible individuals, some components of the flora can become a liability and contribute to the pathogenesis of various intestinal disorders, including inflammatory bowel diseases. It follows that manipulation of the flora to enhance the beneficial components represents a promising therapeutic strategy. The flora has a collective metabolic activity equal to a virtual organ within an organ, and the mechanisms underlying the conditioning influence of the bacteria on mucosal homeostasis and immune responses are beginning to be unravelled. An improved understanding of this hidden organ will reveal secrets that are relevant to human health and to several infectious, inflammatory and neoplastic disease processes.

Mediators of endoplasmic reticulum stress-induced apoptosis.

Abstract: The efficient functioning of the endoplasmic reticulum (ER) is essential for most cellular activities and survival. Conditions that interfere with ER function lead to the accumulation and aggregation of unfolded proteins. ER transmembrane receptors detect the onset of ER stress and initiate the unfolded protein response (UPR) to restore normal ER function. If the stress is prolonged, or the adaptive response fails, apoptotic cell death ensues. Many studies have focused on how this failure initiates apoptosis, as ER stress-induced apoptosis is implicated in the pathophysiology of several neurodegenerative and cardiovascular diseases. In this review, we examine the role of the molecules that are activated during the UPR in order to identify the molecular switch from the adaptive phase to apoptosis. We discuss how the activation of these molecules leads to the commitment of death and the mechanisms that are responsible for the final demise of the cell.

Aβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathology

Abstract: We have generated a novel transgenic mouse model on a C57BL/6J genetic background that coexpresses KM670/671NL mutated amyloid precursor protein and L166P mutated presenilin 1 under the control of a neuron-specific Thy1 promoter element (APPPS1 mice). Cerebral amyloidosis starts at 6–8 weeks and the ratio of human amyloid (A)β42 to Aβ40 is 1.5 and 5 in pre-depositing and amyloid-depositing mice, respectively. Consistent with this ratio, extensive congophilic parenchymal amyloid but minimal amyloid angiopathy is observed. Amyloid-associated pathologies include dystrophic synaptic boutons, hyperphosphorylated tau-positive neuritic structures and robust gliosis, with neocortical microglia number increasing threefold from 1 to 8 months of age. Global neocortical neuron loss is not apparent up to 8 months of age, but local neuron loss in the dentate gyrus is observed. Because of the early onset of amyloid lesions, the defined genetic background of the model and the facile breeding characteristics, APPPS1 mice are well suited for studying therapeutic strategies and the pathomechanism of amyloidosis by cross-breeding to other genetically engineered mouse models.

Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family

Abstract: Several of the inhibitor of apoptosis protein (IAP) family members regulate apoptosis in response to various cellular assaults. Some members are also involved in cell signalling, mitosis and targeting proteins to the ubiquitin-proteasome degradation machinery. The most intensively studied family member, X-linked IAP (XIAP), is a potent inhibitor of caspase activity; hence, it is generally assumed that direct caspase inhibition is an important conserved function of most members of the family. Biochemical and structural studies have precisely mapped the elements of XIAP required for caspase inhibition. Intriguingly, these elements are not conserved among IAPs. Here, we review current knowledge of the caspase-inhibitory potential of the human IAPs and show that XIAP is probably the only bona fide caspase inhibitor, suggesting that the other family members never gained the ability to directly inhibit caspase activity.

Psychrophilic microorganisms: challenges for life

Abstract: The ability of psychrophiles to survive and proliferate at low temperatures implies that they have overcome key barriers inherent to permanently cold environments. These challenges include: reduced enzyme activity; decreased membrane fluidity; altered transport of nutrients and waste products; decreased rates of transcription, translation and cell division; protein cold-denaturation; inappropriate protein folding; and intracellular ice formation. Cold-adapted organisms have successfully evolved features, genotypic and/or phenotypic, to surmount the negative effects of low temperatures and to enable growth in these extreme environments. In this review, we discuss the current knowledge of these adaptations as gained from extensive biochemical and biophysical studies and also from genomics and proteomics.

Cleavage of the siRNA passenger strand during RISC assembly in human cells.

Abstract: A crucial step in the RNA interference (RNAi) pathway involves the assembly of RISC, the RNA-induced silencing complex. RISC initially recognizes a double-stranded short interfering RNA (siRNA), but only one strand is finally retained in the functional ribonucleoprotein complex. The non-incorporated strand, or 'passenger' strand, is removed during the assembly process and most probably degraded thereafter. In this report, we show that the passenger strand is cleaved during the course of RISC assembly following the same rules established for the siRNA-guided cleavage of a target RNA. Chemical modifications impairing the cleavage of the passenger strand also impair the cleavage of a target RNA in vitro as well as the silencing of a reporter gene in vivo, suggesting that passenger strand removal is facilitated by its cleavage during RISC assembly. Interestingly, target RNA cleavage can be rescued if an otherwise non-cleavable passenger strand shows a nick at the scissile phosphodiester bond, which further indicates that the cleavage event per se is not essential.

Tudor, MBT and chromo domains gauge the degree of lysine methylation

Abstract: The post-translational modification of histones regulates many cellular processes, including transcription, replication and DNA repair. A large number of combinations of post-translational modifications are possible. This cipher is referred to as the histone code. Many of the enzymes that lay down this code have been identified. However, so far, few code-reading proteins have been identified. Here, we describe a protein-array approach for identifying methyl-specific interacting proteins. We found that not only chromo domains but also tudor and MBT domains bind to methylated peptides from the amino-terminal tails of histones H3 and H4. Binding specificity observed on the protein-domain microarray was corroborated using peptide pull-downs, surface plasma resonance and far western blotting. Thus, our studies expose tudor and MBT domains as new classes of methyl-lysine-binding protein modules, and also demonstrates that protein-domain microarrays are powerful tools for the identification of new domain types that recognize histone modifications.

Mucin-type O-glycans in human colon and breast cancer: glycodynamics and functions.

Abstract: The glycoproteins of tumour cells are often abnormal, both in structure and in quantity. In particular, the mucin-type O-glycans have several cancer-associated structures, including the T and Tn antigens, and certain Lewis antigens. These structural changes can alter the function of the cell, and its antigenic and adhesive properties, as well as its potential to invade and metastasize. Cancer-associated mucin antigens can be exploited in diagnosis and prognosis, and in the development of cancer vaccines. The activities and Golgi localization of glycosyltransferases are the basis for the glycodynamics of cancer cells, and determine the ranges and amounts of specific O-glycans produced. This review focuses on the glycosyltransferases of colon and breast cancer cells that determine the pathways of mucin-type O-glycosylation, and the proposed functional and pathological consequences of altered O-glycans.

The role of glutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stress.

Abstract: Glutathione is a ubiquitous molecule found in all parts of the cell where it fulfils a range of functions from detoxification to protection from oxidative damage. It provides the main redox buffer for cells and as such has been implicated in the formation of native disulphide bonds. However, the discovery of the enzyme Ero1 has called into question the exact role of glutathione in this process. In this review, we discuss the arguments for and against a role for glutathione in facilitating disulphide-bond formation and consider its role in protecting the cell from endoplasmic-reticulum-generated oxidative stress.

MAPK signalling: ERK5 versus ERK1/2.

Abstract: Extracellular-signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family and, similar to ERK1/2, has the Thr–Glu–Tyr (TEY) activation motif. Both ERK5 and ERK1/2 are activated by growth factors and have an important role in the regulation of cell proliferation and cell differentiation. Moreover, both the ERK5 and the ERK1/2 pathways are sensitive to PD98059 and U0126, which are two well-known inhibitors of the ERK pathway. Despite these similarities, recent studies have revealed distinctive features of the ERK5 pathway: ERK5 has a key role in cardiovascular development and neural differentiation; ERK5 nuclear translocation is controlled by its own nuclear localizing and nuclear export activities; and the carboxy-terminal half of ERK5, which follows its kinase catalytic domain, has a unique function.

MARCH‐V is a novel mitofusin 2‐ and Drp1‐binding protein able to change mitochondrial morphology

Abstract: Mitofusins and Drp1 are key components in mitochondrial membrane fusion and division, but the molecular mechanism underlying the regulation of their activities remains to be clarified. Here, we identified human membrane-associated RING-CH (MARCH)-V as a novel transmembrane protein of the mitochondrial outer membrane. Immunoprecipitation studies demonstrated that MARCH-V interacts with mitofusin 2 (MFN2) and ubiquitinated forms of Drp1. Overexpression of MARCH-V promoted the formation of long tubular mitochondria in a manner that depends on MFN2 activity. By contrast, mutations in the RING finger caused fragmentation of mitochondria. We also show that MARCH-V promotes ubiquitination of Drp1. These results indicate that MARCH-V has a crucial role in the control of mitochondrial morphology by regulating MFN2 and Drp1 activities.

Cisgenic plants are similar to traditionally bred plants: International regulations for genetically modified organisms should be altered to exempt cisgenesis

Abstract: ![][1] ![][2] ![][3] The testing and release of genetically modified organisms (GMOs)—in particular GM plants—is tightly regulated internationally to prevent any negative effects on the environment or human health. However, these regulations are based on transgenic organisms and do not discriminate between transgenic plants and cisgenic plants, although we believe that they are fundamentally different (see sidebarNow, cisgenic plants fall under regulations designed for transgenic organisms, possibly because there have not yet been any applications for the approval of the deliberate release of cisgenic plants into the environment. Definitions of key terms in relation to plants Cisgenesis is the genetic modification of a recipient plant with a natural gene from a crossable—sexually compatible—plant. Such a gene includes its introns and is flanked by its native promoter and terminator in the normalsense orientation.Cisgenic plants can harbour one or more cisgenes, but they do not contain any transgenes. Transgenesis is the genetic modification of a recipient plant with one or more genes from any non‐plant organism, or from a donor plant that is sexually incompatible with the recipient plant. This includes gene sequences of any origin in the anti‐sense orientation, any artificial combination of a coding sequence and a regulatory sequence, such as a promoter from another gene, or a synthetic gene. Traditional breeding encompasses all plant breeding methods that do not fall under current GMO regulations.As the European legal framework defines GMOs and specifies various breeding techniques that are excluded from the GMO regulations,we use this framework as a starting point, particularly the European Directive 2001/18/EC on the deliberate release of GMOs into the environment (European Parliament, 2001). Excluded from this GMO Directive are longstanding cross breeding, in vitro fertilization, polyploidy induction,mutagenesis and fusion of protoplasts from sexually compatible plants (European Parliament, 2001). Although transgenesis and cisgenesis both use the same genetic … [1]: /embed/graphic-1.gif [2]: /embed/graphic-2.gif [3]: /embed/graphic-3.gif

SERRATE: a new player on the plant microRNA scene.

Abstract: MicroRNAs (miRNAs) function as sequence-specific guides that control gene expression by post-transcriptional gene silencing. Many miRNAs influence plant development by regulating the accumulation of transcripts that encode transcription factors. Mutants defective in miRNA accumulation, such as dcl1, hen1, hyl1 and ago1, have pleiotropic developmental phenotypes. The serrate-1 (se-1) mutant of Arabidopsis also shows a highly pleiotropic phenotype, which overlaps with the phenotypes of mutants defective in miRNA accumulation. Although it has been proposed that SERRATE (SE) functions specifically in miRNA-mediated repression of the leaf polarity genes PHABULOSA and PHAVOLUTA, microarray analysis shows upregulation of many genes known to be the targets of miRNAs in se-1. We show that SE is a general regulator of miRNA levels affecting the processing of primary miRNA to miRNA.

RNA interference-inducing hairpin RNAs in plants act through the viral defence pathway

Abstract: RNA interference (RNAi) is widely used to silence genes in plants and animals. It operates through the degradation of target mRNA by endonuclease complexes guided by approximately 21 nucleotide (nt) short interfering RNAs (siRNAs). A similar process regulates the expression of some developmental genes through approximately 21 nt microRNAs. Plants have four types of Dicer-like (DCL) enzyme, each producing small RNAs with different functions. Here, we show that DCL2, DCL3 and DCL4 in Arabidopsis process both replicating viral RNAs and RNAi-inducing hairpin RNAs (hpRNAs) into 22-, 24- and 21 nt siRNAs, respectively, and that loss of both DCL2 and DCL4 activities is required to negate RNAi and to release the plant's repression of viral replication. We also show that hpRNAs, similar to viral infection, can engender long-distance silencing signals and that hpRNA-induced silencing is suppressed by the expression of a virus-derived suppressor protein. These findings indicate that hpRNA-mediated RNAi in plants operates through the viral defence pathway.

Who are we? Indigenous microbes and the ecology of human diseases.

Abstract: Diseases date back to the dawn of humankind. As humans have evolved, so too have their diseases: some that were once rare have become common, others have disappeared and new varieties have emerged. Many of these changes have taken place in the wake of important transformations in human civilizations and ecology. It is therefore feasible to propose that diseases succeed and fail in response to humanity's advances. My hypothesis to explain the appearance and disappearance of some of these diseases—both infectious and chronic—is that changes in human ecology result in changes in the microbes that populate our bodies. This, in turn, affects our physiology and ultimately our health. > …diseases succeed and fail in response to humanity's advances The invention of agriculture about 10,000 years ago led to a massive increase in the human population, but at a price: by living in closer proximity to domesticated animals and those that parasitized their food supply (such as rats), humans became more susceptible to measles, plague, tuberculosis and other zoonoses. Urbanization during the Middle Ages was one of the main factors facilitating the devastating spread of Yersinia pestis through the crowded cities of Europe—the Black Death subsequently killed about 30% of the continent's population. Improved hygiene in the nineteenth century eventually reduced the prevalence of plague, along with cholera, dysentery, materno‐fetal mortality, childhood infections and other ancient foes. The agricultural revolution after the Second World War relegated famine and its associated diseases—such as pellagra, which is a deficiency of niacin—to history, at least in the industrialized world. ![][1] In the nineteenth and twentieth centuries, industrialization—and the scientific revolution that preceded and facilitated it—also gave humans new tools for controlling infectious diseases. Due to improvements in sanitation, antibiotics and vaccines, smallpox has now been eradicated, polio is on the brink of extinction and many other … [1]: /embed/graphic-1.gif

Genome-wide natural antisense transcription: coupling its regulation to its different regulatory mechanisms

Abstract: Many genomic loci contain transcription units on both strands, therefore two oppositely oriented transcripts can overlap. Often, one strand codes for a protein, whereas the transcript from the other strand is non-encoding. Such natural antisense transcripts (NATs) can negatively regulate the conjugated sense transcript. NATs are highly prevalent in a wide range of species—for example, around 15% of human protein-encoding genes have an associated NAT. The regulatory mechanisms by which NATs act are diverse, as are the means to control their expression. Here, we review the current understanding of NAT function and its mechanistic basis, which has been gathered from both individual gene cases and genome-wide studies. In parallel, we survey findings about the regulation of NAT transcription. Finally, we hypothesize that the regulation of antisense transcription might be tailored to its mode of action. According to this model, the observed relationship between the expression patterns of NATs and their targets might indicate the regulatory mechanism that is in action.

ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells.

Abstract: Lipid droplets (LDs), also called adiposomes, are found in many eukaryotic cells, and are highly upregulated in lipid-storage cells, such as adipocytes. The mechanism by which adiposomes and their component neutral lipids are degraded is an important health issue with the rapidly spreading epidemic of obesity. Recently, a novel triglyceride lipase (adipose triglyceride lipase (ATGL)) that catalyses the initial step in triglyceride hydrolysis in adipocyte LDs was identified. Here, we show that ATGL also functions in non-adipocyte cells, and has an important role in LD degradation in these cells. Overexpression of wild-type ATGL causes a marked decrease in LD size, whereas a catalytically inactive mutant retains the ability to localize to LDs, but is unable to decrease their size. Depletion of ATGL by RNA interference leads to a significant increase in the size of LDs. These results show that ATGL has an important role in LD/adiposome turnover in mammalian cells.

Alarmin(g) news about danger: workshop on innate danger signals and HMGB1.

Abstract: The EMBO Workshop on Innate Danger Signals and HMGB1 took place between 8 and 11 February 2006 in Milan, Italy, and was organized by M. Bianchi, K. Tracey and U. Andersson. ![][1] During evolution, multicellular organisms have developed mechanisms to counteract life‐threatening events, such as infections and tissue injury, as well as to restore tissue homeostasis. These mechanisms are called ‘the inflammatory response‘. To initiate an appropriate inflammatory response, organisms have developed ways to recognize potentially life‐threatening events. Danger signals—the molecules that alert the innate immune system and trigger defensive immune responses—have been classically defined as exogenous, pathogen‐associated molecular pattern (PAMP) molecules. PAMPs—for example, lipopolysacharide (LPS), viral RNA and bacterial petidoglycans—interact with dedicated receptors on immune cells, the so‐called pattern recognition receptors (PRRs). On ligation, PRRs transduce activation signals that lead to the production of proinflammatory molecules such as tumour necrosis factor (TNF). A well‐known family of PRRs is the toll‐like receptor (TLR) family in which each member recognizes a specific set of PAMPs. However, several endogenous molecules also initiate inflammatory responses by interacting with signalling receptors; such innate danger signals are known as endokines and/or alarmins. The term endokine reflects the potential of these molecules with intranuclear and/or intracellular functions also to act extracellularly, in this case to be immunostimulatory on their release from necrotic cells. The endokine family includes high‐mobility‐group box (HMGB) proteins, interleukins such as IL‐1α, cytosolic calcium‐binding proteins of the S100 family, heat‐shock proteins (HSPs) and nucleosomes. The term alarmin, coined by J. Oppenheim (Frederick, MD, USA) and co‐workers, denotes an array of structurally diverse multifunctional host proteins that are rapidly released during infection or tissue damage, and that have mobilizing and activating effects on receptor‐expressing cells engaged in host defence and tissue repair. Innate‐immune mediators that have alarmin function include defensins, eosinophil‐derived neurotoxin, cathelicidins and HMGB1 … [1]: /embed/graphic-1.gif

Different Polycomb group complexes regulate common target genes in Arabidopsis.

Abstract: Polycomb group (PcG) proteins convey epigenetic inheritance of repressed transcriptional states. Although the mechanism of the action of PcG is not completely understood, methylation of histone H3 lysine 27 (H3K27) is important in establishing PcG-mediated transcriptional repression. We show that the plant PcG target gene PHERES1 is regulated by histone trimethylation on H3K27 residues mediated by at least two different PcG complexes in plants, containing the SET domain proteins MEDEA or CURLY LEAF/SWINGER. Furthermore, we identify FUSCA3 as a potential PcG target gene and show that FUSCA3 is regulated by MEDEA and CURLY LEAF/SWINGER. We propose that different PcG complexes regulate a common set of target genes during the different stages of plant development.

ARE‐mRNA degradation requires the 5′–3′ decay pathway

Abstract: As an important mode of suppressing gene expression, messenger RNAs containing an AU-rich element (ARE) in the 3′ untranslated region are rapidly degraded in the cytoplasm. ARE-mediated mRNA decay (AMD) is initiated by deadenylation, and in vitro studies have indicated that subsequent degradation occurs in the 3′–5′ direction through a complex of exonucleases termed the exosome. An alternative pathway of mRNA degradation occurs at processing bodies, cytoplasmic foci that contain decapping enzymes, the 5′–3′ exonuclease Xrn1 and the Lsm1–7 heptamer. To determine which of the two pathways is important for AMD in live cells, we targeted components of both pathways using short interfering RNA in human HT1080 cells. We show that Xrn1 and Lsm1 are essential for AMD. On the other side, out of three exosome components tested, only knockdown of PmScl-75 caused a strong inhibition of AMD. Our results show that mammalian cells, similar to yeast, require the 5′–3′ Xrn1 pathway to degrade ARE-mRNAs.

Western science and traditional knowledge. Despite their variations, different forms of knowledge can learn from each other.

Abstract: Cultures from all over the world have developed different views of nature throughout human history. Many of them are rooted in traditional systems of beliefs, which indigenous people use to understand and interpret their biophysical environment (Iaccarino, 2003). These systems of managing the environment constitute an integral part of the cultural identity and social integrity of many indigenous populations. At the same time, their knowledge embodies a wealth of wisdom and experience of nature gained over millennia from direct observations, and transmitted—most often orally—over generations. The importance of this traditional knowledge for the protection of biodiversity and the achievement of sustainable development is slowly being recognized internationally (Gadgil et al , 1993). For example, Article 8 of the Convention on Biological Diversity urges us to “…respect, preserve and maintain knowledge, innovations and practices of indigenous and local communities embodying traditional lifestyles relevant for the conservation and sustainable use of biological diversity….” (United Nations, 1992). In addition, traditional or indigenous knowledge has been rediscovered as a model for a healthy interaction with, and use of, the environment, and as a rich source to be tapped into in order to gain new perspectives about the relationship between humans and nature. However, our difficulty in approaching the knowledge from indigenous cultures is already reflected in the way in which we describe and name it. No universal definition is available, and many terms are used to establish what indigenous people know (Berkes, 1993), including traditional knowledge or traditional ecological knowledge, local knowledge, indigenous knowledge or science, folk knowledge, farmers' knowledge, fishers' knowledge and tacit knowledge. Each of these terms carries different implications, and there is an ensuing discussion about which one is the most appropriate. The word ‘traditional’, for example, places the emphasis on the transmission of knowledge along a cultural continuity, but might ignore …

Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains.

Abstract: Deltex (DTX) and AIP4 are the human orthologues of the Drosophila deltex and Suppressor of deltex, which have been genetically described as being antagonistically involved in the Notch signalling pathway. Both genes encode E3 ubiquitin ligases of the RING (Really interesting new gene)-H2 and HECT (Homologous to E6AP carboxyl terminus) families, respectively. In an attempt to understand the molecular basis of their genetic interactions, we studied the relationship between DTX and AIP4 in the absence of activation of the Notch pathway. We show here that both molecules interact and partially colocalize to endocytic vesicles, and that AIP4 targets DTX for lysosomal degradation. Furthermore, AIP4-generated polyubiquitin chains are mainly conjugated through lysine 29 of ubiquitin in vivo, indicating a link between this type of chain and lysosomal degradation.

Yeast Gal4: a transcriptional paradigm revisited

Abstract: During the past two decades, the yeast Gal4 protein has been used as a model for studying transcriptional activation in eukaryotes. Many of the properties of transcriptional regulation first demonstrated for Gal4 have since been shown to be reiterated in the function of several other eukaryotic transcriptional regulators. Technological advances based on the transcriptional properties of this factor—such as the two-hybrid technology and Gal4-inducible systems for controlled gene expression—have had far-reaching influences in fields beyond transcription. In this review, we provide an updated account of Gal4 function, including data from new technologies that have been recently applied to the study of the GAL network.

Two internal ribosome entry sites mediate the translation of p53 isoforms

Abstract: The p53 tumour suppressor protein has a crucial role in cell-cycle arrest and apoptosis. Previous reports show that the p53 messenger RNA is translated to produce an amino-terminal-deleted isoform (ΔN-p53) from an internal initiation codon, which acts as a dominant-negative inhibitor of full-length p53. Here, we show that two internal ribosome entry sites (IRESs) mediate the translation of both full-length and ΔN-p53 isoforms. The IRES directing the translation of full-length p53 is in the 5′-untranslated region of the mRNA, whereas the IRES mediating the translation of ΔN-p53 extends into the protein-coding region. The two IRESs show distinct cell-cycle phase-dependent activity, with the IRES for full-length p53 being active at the G2–M transition and the IRES for ΔN-p53 showing highest activity at the G1–S transition. These results indicate a novel translational control of p53 gene expression and activity.

The role of synaptic ion channels in synaptic plasticity.

Abstract: The nervous system receives a large amount of information about the environment through elaborate sensory routes. Processing and integration of these wide-ranging inputs often results in long-term behavioural alterations as a result of past experiences. These relatively permanent changes in behaviour are manifestations of the capacity of the nervous system for learning and memory. At the cellular level, synaptic plasticity is one of the mechanisms underlying this process. Repeated neural activity generates physiological changes in the nervous system that ultimately modulate neuronal communication through synaptic transmission. Recent studies implicate both presynaptic and postsynaptic ion channels in the process of synapse strength modulation. Here, we review the role of synaptic ion channels in learning and memory, and discuss the implications and significance of these findings towards deciphering the molecular biology of learning and memory.

The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling

Abstract: Metazoans rapidly respond to changes in oxygen availability by regulating gene expression. The transcription factor hypoxia-inducible-factor (HIF), which controls the expression of several genes, ‘senses' the oxygen concentration indirectly through the hydroxylation of two proline residues that earmarks the HIF-α subunits for proteasomal degradation. We review the expression, regulation and function of the HIF prolyl hydroxylases or prolyl hydroxylases domain proteins, which are genuine oxygen sensors.

Organellar proteomics: turning inventories into insights

Abstract: Subcellular organization is yielding to large-scale analysis. Researchers are now applying robust mass-spectrometry-based proteomics methods to obtain an inventory of biochemically isolated organelles that contain hundreds of proteins. High-resolution methods allow accurate protein identification, and novel algorithms can distinguish genuine from co-purifying components. Organellar proteomes have been analysed by bioinformatic methods and integrated with other large-scale data sets. The dynamics of organelles can also be studied by quantitative proteomics, which offers powerful methods that are complementary to fluorescence-based microscopy. Here, we review the emerging trends in this rapidly expanding area and discuss the role of organellar proteomics in the context of functional genomics and systems biology.

Transcription in four dimensions: nuclear receptor-directed initiation of gene expression

Abstract: Regulated gene expression, achieved through the coordinated assembly of transcription factors, co-regulators and the basal transcription machinery on promoters, is an initial step in accomplishing cell specificity and homeostasis. Traditional models of transcriptional regulation tend to be static, although gene expression profiles change with time to adapt to developmental and environmental cues. Furthermore, biochemical and structural studies have determined that initiation of transcription progresses through a series of ordered events. By integrating time into the analysis of transcription, chromatin immunoprecipitation assays and live-cell imaging techniques have revealed the dynamic, cooperative, functionally redundant and cyclical nature of gene expression. In this review, we present a dynamic model of gene transcription that integrates data obtained by these two techniques.

Survivin mediates targeting of the chromosomal passenger complex to the centromere and midbody

Abstract: The chromosomal passenger complex (CPC) coordinates chromosomal and cytoskeletal events of mitosis. The enzymatic core of this complex (Aurora-B) is guided through the mitotic cell by its companion chromosomal passenger proteins, inner centromere protein (INCENP), Survivin and Borealin/Dasra-B, thereby allowing it to act at the right place at the right time. Here, we addressed the individual contributions of INCENP, Survivin and Borealin to the proper functioning of this complex. We show that INCENP has an important role in stabilizing the complex, and that Borealin acts to promote binding of Survivin to INCENP. Importantly, when Survivin is directly fused to INCENP, this hybrid can restore CPC function at the centromeres and midbody, even in the absence of Borealin and the centromere-targeting domain of INCENP. Thus, Survivin is an important mediator of centromere and midbody docking of Aurora-B during mitosis.

P53 modulates homologous recombination by transcriptional regulation of the RAD51 gene

Abstract: DNA repair by homologous recombination is involved in maintaining genome stability. Previous data report that wild-type p53 suppresses homologous recombination and physically interacts with Rad51. Here, we show the in vivo binding of wild-type p53 to a p53 response element in the promoter of Rad51 and the downregulation of Rad51 messenger RNA and protein by wild-type p53, favoured by DNA damage. Moreover, wild-type p53 inhibits Rad51 foci formation in response to double-strand breaks, whereas p53 contact mutant R280K fails to repress Rad51 mRNA and protein expression and Rad51 foci formation. We propose that transcriptional repression of Rad51 by p53 participates in regulating homologous recombination, and impaired Rad51 repression by p53 mutants may contribute to malignant transformation.