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In brief: July 2008Cytoskeleton Capping protein increases the rate of actin-based motility by promoting filament nucleation by the Arp2/3 complex Capping protein (CP), which caps barbed ends of actin filaments and terminates actin filament elongation, actually promotes actin-based motility. To investigate this apparent paradox, the authors used an actin-based motility system that was reconstituted using purified components, including CP and the actin-related protein-2/3 (ARP2/3) complex. CP does not increase the rate of motility by increasing the rate of elongation of uncapped actin filaments as previously thought, but instead promotes actin filament nucleation by the ARP2/3 complex. This also implies that the rate of motility can be uncoupled from the rate of actin network assembly. Stem cells The ground state of embryonic stem cell self-renewal Embryonic stem cell (ESC) self-renewal is thought to require a number of external stimuli, including cytokines (which activate STAT3) and growth factors. However, Ying et al. now demonstrate that both wild-type and Stat3-/- mouse ESCs show robust self-renewal in the presence of inhibitors that eliminate differentiation-inducing signalling from mitogen-activated protein kinase and glycogen synthase kinase-3. These findings suggest that external stimuli shield the pluripotent ESC state from differentiation and that ESCs have an intrinsic ability to self-renew, which is also reflected by their tumorigenic potential. Chemotherapy Dasatinib crosses the blood–brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia The treatment of Philadelphia chromosome (Ph)+ leukaemia is complicated by the fact that the gold-standard treatment imatinib, a BCR–ABL tyrosine kinase inhibitor, cannot effectively cross the blood–brain barrier and thus cannot prevent central nervous system (CNS) relapse. Dasatinib, a dual-specificity SRC and BCR–ABL kinase inhibitor, however, demonstrated activity in clinical trials of patients with Ph+ CNS leukaemia. In total, 11 of 14 patients achieved long-lasting remission. The authors conclude that dasatinib is a promising therapeutic option in patients with intercranial leukaemia and those experiencing CNS relapse while on imatinib. DNA repair Mdm2 promotes genetic instability and transformation independently of p53 p53-independent functions of MDM2 remain poorly understood. This study implicates MDM2 in DNA repair through association with NBS1, a component of the MRE11–RAD50–NBS1 DNA repair complex. Upon DNA damage, MDM2 overexpression in p53-null cells led to a reduction in the number of Human disease Towards a transgenic model of Huntington's disease in a non-human primate
Although mouse and fly models of Huntington disease (HD) have helped to understand the molecular basis of this triplet-repeat disorder, these models do not replicate all the behavioural changes seen in humans. The first non-human primate model of HD has now been created by inserting an expanded exon of the human huntingtin gene into unfertilized macaque eggs. The animals show many clinical features of HD and so could be used to explore disease pathogenesis and potential treatments. Human disease XPD helicase structures and activities: insights into the cancer and aging phenotypes from XPD mutations
Structure of the DNA repair helicase XPD.
The structural and enzymatic study of the archaeal homologue of the human xeroderma pigmentosa protein (XPD) explains how point mutations in this helicase cause three distinct human disorders. XP-causing mutations disable the DNA-repair function, leaving individuals prone to cancer; the two ageing disorders Cockayne syndrome and trichothiodystrophy arise when the enzyme is, respectively, defective in protein–protein interactions, causing defects in transcription and repair, or locked in position so that DNA is repaired rather than transcribed. Epigenetics Genome-wide analysis reveals MOF as a key regulator of dosage compensation and gene expression in Drosophila
Dosage compensation in Drosophila involves upregulation of the genes on the single X chromosome in males, and this is known to be associated with hyperacetylation of histones. The authors carried out chromatin immunoprecipitation and microarray analyses for the position and the effects of binding of the conserved histone acetyltransferase MOF, and found that it binds differentially to male and female X chromosomes. This is likely to be an important step in establishing differential gene expression. Epigenetics MeCP2, a key contributor to neurological disease, activates and represses transcription Methyl-CpG-binding protein 2 (MECP2) is a transcriptional regulator that is essential for brain development. The authors examined changes in gene expression in the hypothalamus of mice that either lacked or overexpressed MECP2. MECP2 regulated a large number of genes, and activated more genes than it repressed. The authors also showed that CREB1 is a direct target of MECP2. As MECP2 was previously thought to be mainly a transcriptional repressor, these findings might have consequences for the treatment of syndromes that result from abnormal MECP2 expression. Synaptic plasticity Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus Endocannabinoids (eCBs) can modulate synaptic plasticity, but how eCB mobilization is regulated has remained unclear. Here, the authors demonstrated that eCB mobilization in CA1 pyramidal cells by group I metabotropic glutamate receptors (mGluRs) required the cells to be primed by a transient increase in intracellular Ca2+ concentrations. Furthermore, prior mGluR activation potentiated Ca2+-dependent eCB mobilization. These findings identify a mechanism for regulating eCB mobilization. Molecular neuroscience The microRNA miR-1 regulates a MEF-2-dependent retrograde signal at neuromuscular junctions MicroRNAs seem to regulate many aspects of neural development. Here, the authors showed that synaptic transmission at neuromuscular junctions was reduced in Caenorhabditis elegans that lacked miR-1. This was associated with altered expression of nicotinic acetylcholine (Ach) receptor subunits and with altered expression of the transcription factor MEF2. MEF2 regulates presynaptic ACh release, probably by modulating the activity of the synaptic vesicle protein RAB3. These findings suggest that miR-1 regulates synaptic function at neuromuscular junctions through a nicotinic signalling pathway. Anticancer drugs Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator Lain and colleagues carried out a cell-based screen to identify small molecules that activate the tumour suppressor p53. Two hits — tenovin-1 and the more water-soluble analogue tenovin-6 — were shown to act through inhibition of the protein-deacetylating activities of sirtuin-1 and -2. Tenovin-6 decreased melanoma-cell-derived tumour growth in vivo as a single agent. This study highlights the utility of tenovins as biological tools for the study of sirtuin function and their potential therapeutic use. Virtual screening Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening The histamine H4 receptor is a promising target for the treatment of allergy and inflammation, but only a limited number of H4-selective ligands have been discovered. Kiss and colleagues report a large scale, structure-based virtual screen on a homology model of the H4 receptor. More than 8.7 million 3D structures derived from different vendor databases were investigated by docking to the H4 receptor binding site. From a total of 255 selected compounds, 16 had in vitro affinity and several novel scaffolds were identified that could be used to develop selective H4 ligands. Mutagenesis A better knockout mouse Inducible gene targeting in mice is time-consuming and can be unreliable. Zeng et al. now describe an improved conditional and reversible tetracycline-based system called iKO to generate knockout mice. It boasts more tightly regulated expression of the gene of interest, powered by the gene's own promoter, so there is no need to worry about leakage or tissue specificity. This should be especially welcome news to the mouse community. Innate immunity A Toll-like receptor 2–integrin Toll-like receptor 2 (TLR2) mediates the inflammatory response to a range of pathogen-associated molecular patterns (PAMPs), including bacterial lipopeptides. For some TLRs, such as TLR4, how the receptor recognizes PAMPs is well understood. In a study that was recently published in Nature Immunology, Gisa Gerold and colleagues have now shed new light on TLR2 recognition of PAMPs. Gerold et al. demonstrated that two additional host proteins are involved: vitronectin and integrin Signalling in space Signal transduction at point-blank range: Analysis of a spatial coupling mechanism for pathway crosstalk Intracellular signalling pathways often depend on enzymes that are recruited by plasma membrane receptors and act upon membrane-associated substrates. Thus, the membrane acts as a physical platform for interactions taking place at the early stages of receptor-mediated signalling, bringing enzymes closer to their substrates. Existing models that describe enzyme-catalysed reactions at cell membranes are based on the rate of lateral diffusion of membrane-associated molecules being the limiting factor. As reported in Biophysical Journal, Michael Monine and Jason Haugh have now developed a quantitative model that expands on the role of diffusion-controlled kinetics — a two-dimensional Brownian dynamics kinetic model. The model introduces 'spatial coupling' whereby simultaneous recruitment of different enzymes to the same receptor facilitates cross-talk between different signalling pathways. The authors analysed the specific case of phosphoinositide 3-kinase (PI3K), which is localised as a result of cooperative interactions between receptors and active Ras. The assembly of receptor/PI3K/Ras complexes is facilitated by the local action of a guanine exchange factor (GEF) bound to the same receptor. Spatial coupling between GEF and PI3K relies on Ras being first released by a receptor-bound GEF and then captured by a PI3K molecule associated with the same receptor. The authors were thus able to evaluate the probabilities of short- and long-range interactions to characterise spatial coupling. | |
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H2AX foci and decreased levels of activated ATM, and ATM and ATR downstream target proteins. These defects resulted in increased chromosome and chromatid breaks, attenuated DNA repair and enhanced transformation. Interestingly, these effects do not require the E3-ligase activity of MDM2, suggesting the involvement of alternative mechanisms that warrant elucidation. The inhibition of MDM2 is an exciting therapeutic strategy that has led to the development of small molecules such as the Nutlins, which interfere with the MDM2–p53 interaction. These data suggest that the efficacy of such treatments may be further improved by modulation of the MDM2–NSB1 complex in patients whose tumours overexpress MDM2.
3 complex senses bacterial lipopeptides via vitronectin