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781.
The harlequin mouse mutation downregulates apoptosis-inducing factor 总被引:35,自引:0,他引:35
Klein JA Longo-Guess CM Rossmann MP Seburn KL Hurd RE Frankel WN Bronson RT Ackerman SL 《Nature》2002,419(6905):367-374
Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. We have identified the Hq mutation as a proviral insertion in the apoptosis-inducing factor (Aif) gene, causing about an 80% reduction in AIF expression. Mutant cerebellar granule cells are susceptible to exogenous and endogenous peroxide-mediated apoptosis, but can be rescued by AIF expression. Overexpression of AIF in wild-type granule cells further decreases peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice show oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice re-enter the cell cycle before undergoing apoptosis. Our results provide a genetic model of oxidative stress-mediated neurodegeneration and demonstrate a direct connection between cell cycle re-entry and oxidative stress in the ageing central nervous system. 相似文献
782.
Active genes are tri-methylated at K4 of histone H3 总被引:92,自引:0,他引:92
Santos-Rosa H Schneider R Bannister AJ Sherriff J Bernstein BE Emre NC Schreiber SL Mellor J Kouzarides T 《Nature》2002,419(6905):407-411
Lysine methylation of histones in vivo occurs in three states: mono-, di- and tri-methyl. Histone H3 has been found to be di-methylated at lysine 4 (K4) in active euchromatic regions but not in silent heterochromatic sites. Here we show that the Saccharomyces cerevisiae Set1 protein can catalyse di- and tri-methylation of K4 and stimulate the activity of many genes. Using antibodies that discriminate between the di- and tri-methylated state of K4 we show that di-methylation occurs at both inactive and active euchromatic genes, whereas tri-methylation is present exclusively at active genes. It is therefore the presence of a tri-methylated K4 that defines an active state of gene expression. These findings establish the concept of methyl status as a determinant for gene activity and thus extend considerably the complexity of histone modifications. 相似文献
783.
Bird AW Yu DY Pray-Grant MG Qiu Q Harmon KE Megee PC Grant PA Smith MM Christman MF 《Nature》2002,419(6905):411-415
784.
TRPV3 is a calcium-permeable temperature-sensitive cation channel 总被引:37,自引:0,他引:37
Xu H Ramsey IS Kotecha SA Moran MM Chong JA Lawson D Ge P Lilly J Silos-Santiago I Xie Y DiStefano PS Curtis R Clapham DE 《Nature》2002,418(6894):181-186
Transient receptor potential (TRP) proteins are cation-selective channels that function in processes as diverse as sensation and vasoregulation. Mammalian TRP channels that are gated by heat and capsaicin (>43 degrees C; TRPV1 (ref. 1)), noxious heat (>52 degrees C; TRPV2 (ref. 2)), and cooling (< 22 degrees C; TRPM8 (refs 3, 4)) have been cloned; however, little is known about the molecular determinants of temperature sensing in the range between approximately 22 degrees C and 40 degrees C. Here we have identified a member of the vanilloid channel family, human TRPV3 (hTRPV3) that is expressed in skin, tongue, dorsal root ganglion, trigeminal ganglion, spinal cord and brain. Increasing temperature from 22 degrees C to 40 degrees C in mammalian cells transfected with hTRPV3 elevated intracellular calcium by activating a nonselective cationic conductance. As in published recordings from sensory neurons, the current was steeply dependent on temperature, sensitized with repeated heating, and displayed a marked hysteresis on heating and cooling. On the basis of these properties, we propose that hTRPV3 is thermosensitive in the physiological range of temperatures between TRPM8 and TRPV1. 相似文献
785.
Hon WC Wilson MI Harlos K Claridge TD Schofield CJ Pugh CW Maxwell PH Ratcliffe PJ Stuart DI Jones EY 《Nature》2002,417(6892):975-978
786.
Compared to other ions, protons (H(+)) and hydroxide ions (OH(-)) exhibit anomalously high mobilities in aqueous solutions. On a qualitative level, this behaviour has long been explained by 'structural diffusion' the continuous interconversion between hydration complexes driven by fluctuations in the solvation shell of the hydrated ions. Detailed investigations have led to a clear understanding of the proton transport mechanism at the molecular level. In contrast, hydroxide ion mobility in basic solutions has received far less attention, even though bases and base catalysis play important roles in many organic and biochemical reactions and in the chemical industry. The reason for this may be attributed to the century-old notion that a hydrated OH(-) can be regarded as a water molecule missing a proton, and that the transport mechanism of such a 'proton hole' can be inferred from that of an excess proton by simply reversing hydrogen bond polarities. However, recent studies have identified OH(-) hydration complexes that bear little structural similarity to proton hydration complexes. Here we report the solution structures and transport mechanisms of hydrated hydroxide, which we obtained from first-principles computer simulations that explicitly treat quantum and thermal fluctuations of all nuclei. We find that the transport mechanism, which differs significantly from the proton hole picture, involves an interplay between the previously identified hydration complexes and is strongly influenced by nuclear quantum effects. 相似文献
787.
Release of chromatin protein HMGB1 by necrotic cells triggers inflammation 总被引:129,自引:0,他引:129
High mobility group 1 (HMGB1) protein is both a nuclear factor and a secreted protein. In the cell nucleus it acts as an architectural chromatin-binding factor that bends DNA and promotes protein assembly on specific DNA targets. Outside the cell, it binds with high affinity to RAGE (the receptor for advanced glycation end products) and is a potent mediator of inflammation. HMGB1 is secreted by activated monocytes and macrophages, and is passively released by necrotic or damaged cells. Here we report that Hmgb1(-/-) necrotic cells have a greatly reduced ability to promote inflammation, which proves that the release of HMGB1 can signal the demise of a cell to its neighbours. Apoptotic cells do not release HMGB1 even after undergoing secondary necrosis and partial autolysis, and thus fail to promote inflammation even if not cleared promptly by phagocytic cells. In apoptotic cells, HMGB1 is bound firmly to chromatin because of generalized underacetylation of histone and is released in the extracellular medium (promoting inflammation) if chromatin deacetylation is prevented. Thus, cells undergoing apoptosis are programmed to withhold the signal that is broadcast by cells that have been damaged or killed by trauma. 相似文献
788.
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer 总被引:26,自引:0,他引:26
Tomlinson IP Alam NA Rowan AJ Barclay E Jaeger EE Kelsell D Leigh I Gorman P Lamlum H Rahman S Roylance RR Olpin S Bevan S Barker K Hearle N Houlston RS Kiuru M Lehtonen R Karhu A Vilkki S Laiho P Eklund C Vierimaa O Aittomäki K Hietala M Sistonen P Paetau A Salovaara R Herva R Launonen V Aaltonen LA;Multiple Leiomyoma Consortium 《Nature genetics》2002,30(4):406-410
789.
Screens were made for alcohol dehydrogenase (ADH) of the classical type (the MDR superfamily) in translations of human and other relevant genomes, corresponding to the organism types from which the enzyme was initially purified. Considerable multiplicities were detected in the dimeric enzymes from higher eukaryotes: seven forms in the human (plus three pseudogenes), all genes on chromosome 4, in the order class IV --> class Igamma --> class Ibeta --> class Ialpha --> class V --> class II --> class III, and eight forms in Arabidopsis thaliana (plus one pseudogene). These multiplicity patterns, and the species variability in the animal (human/mouse) and plant (Arabidopsis/pea) lines, suggest parallel but separate duplicatory events, giving rise to three families of dimeric MDR-ADH: class III, the animal non-class III, and the plant non-class III enzymes, with functions in formaldehyde elimination, in alcohol/aldehyde detoxication and in special pathways in higher eukaryotes. Multiplicity, although to a lesser extent, was also noted in tetrameric MDR-ADH, suggesting functional divergence between the dimeric and tetrameric enzymes. Combining these observations, at least five levels of divergence are reflected in the present ADH forms, corresponding to nodes at the SDR/MDR, the dimer/tetramer, the class III/non-class III, the class I/P, and the more recent class splits, each branch associated with separate functional patterns. 相似文献
790.
The copines are a novel family of ubiquitous Ca(2+)-dependent, phospholipid-binding proteins. They contain two Ca(2+)- and phospholipid-binding domains known as 'C2 domains' present in proteins such as protein kinase C, phospholipase C and synaptotagmin. Copines are thought to be involved in membrane-trafficking phenomena because of their phospholipid-binding properties. They may also be involved in protein-protein interactions since they contain a domain similar to the protein-binding 'A domain' of integrins. The biochemistry, gene structure, tissue distribution and possible biological roles of copines are discussed, including recent observations with Arabidopsis that indicate that copines may be involved in cell division and growth. 相似文献