共查询到20条相似文献,搜索用时 19 毫秒
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Puigserver P Rhee J Donovan J Walkey CJ Yoon JC Oriente F Kitamura Y Altomonte J Dong H Accili D Spiegelman BM 《Nature》2003,423(6939):550-555
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Bernardi R Guernah I Jin D Grisendi S Alimonti A Teruya-Feldstein J Cordon-Cardo C Simon MC Rafii S Pandolfi PP 《Nature》2006,442(7104):779-785
Loss of the promyelocytic leukaemia (PML) tumour suppressor has been observed in several human cancers. The tumour-suppressive function of PML has been attributed to its ability to induce growth arrest, cellular senescence and apoptosis. Here we identify PML as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischaemic and neoplastic conditions, through the control of protein translation. We demonstrate that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1alpha (HIF-1alpha) by repressing mammalian target of rapamycin (mTOR). PML physically interacts with mTOR and negatively regulates its association with the small GTPase Rheb by favouring mTOR nuclear accumulation. Notably, Pml-/- cells and tumours display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 and tumour angiogenesis in mouse and human tumours. Thus, our findings identify PML as a novel suppressor of mTOR and neoangiogenesis. 相似文献
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Predicting the consequences of species loss is critically important, given present threats to biological diversity such as habitat destruction, overharvesting and climate change. Several empirical studies have reported decreased ecosystem performance (for example, primary productivity) coincident with decreased biodiversity, although the relative influence of biotic effects and confounding abiotic factors has been vigorously debated. Whereas several investigations focused on single trophic levels (for example, grassland plants), studies of whole systems have revealed multiple layers of feedbacks, hidden drivers and emergent properties, making the consequences of species loss more difficult to predict. Here we report functionally important organisms and considerable biocomplexity in a sedimentary seafloor habitat, one of Earth's most widespread ecosystems. Experimental field measurements demonstrate how the abundance of spatangoid urchins--infaunal (in seafloor sediment) grazers/deposit feeders--is positively related to primary production, as their activities change nutrient fluxes and improve conditions for production by microphytobenthos (sedimentatry microbes and unicellular algae). Declines of spatangoid urchins after trawling are well documented, and our research linking these bioturbators to important benthic-pelagic fluxes highlights potential ramifications for productivity in coastal oceans. 相似文献
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Yoon JC Puigserver P Chen G Donovan J Wu Z Rhee J Adelmant G Stafford J Kahn CR Granner DK Newgard CB Spiegelman BM 《Nature》2001,413(6852):131-138
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本研究构建了一个线粒体基因之间的功能连锁网络,通过该网络来反映基因之间的功能关系,然后利用基于网络的算法计算网络中的基因与线粒体复合物Ⅰ缺陷的相关程度,从而进行疾病基因的预测. 相似文献
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Suzuki K Okuno T Yamamoto M Pasterkamp RJ Takegahara N Takamatsu H Kitao T Takagi J Rennert PD Kolodkin AL Kumanogoh A Kikutani H 《Nature》2007,446(7136):680-684
Semaphorins are axon guidance factors that assist growing axons in finding appropriate targets and forming synapses. Emerging evidence suggests that semaphorins are involved not only in embryonic development but also in immune responses. Semaphorin 7A (Sema7A; also known as CD108), which is a glycosylphosphatidylinositol-anchored semaphorin, promotes axon outgrowth through beta1-integrin receptors and contributes to the formation of the lateral olfactory tract. Although Sema7A has been shown to stimulate human monocytes, its function as a negative regulator of T-cell responses has also been reported. Thus, the precise function of Sema7A in the immune system remains unclear. Here we show that Sema7A, which is expressed on activated T cells, stimulates cytokine production in monocytes and macrophages through alpha1beta1 integrin (also known as very late antigen-1) as a component of the immunological synapse, and is critical for the effector phase of the inflammatory immune response. Sema7A-deficient (Sema7a-/-) mice are defective in cell-mediated immune responses such as contact hypersensitivity and experimental autoimmune encephalomyelitis. Although antigen-specific and cytokine-producing effector T cells can develop and migrate into antigen-challenged sites in Sema7a-/- mice, Sema7a-/- T cells fail to induce contact hypersensitivity even when directly injected into the antigen-challenged sites. Thus, the interaction between Sema7A and alpha1beta1 integrin is crucial at the site of inflammation. These findings not only identify a function of Sema7A as an effector molecule in T-cell-mediated inflammation, but also reveal a mechanism of integrin-mediated immune regulation. 相似文献
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van Rossum DB Patterson RL Sharma S Barrow RK Kornberg M Gill DL Snyder SH 《Nature》2005,434(7029):99-104
Many ion channels are regulated by lipids, but prominent motifs for lipid binding have not been identified in most ion channels. Recently, we reported that phospholipase Cgamma1 (PLC-gamma1) binds to and regulates TRPC3 channels, components of agonist-induced Ca2+ entry into cells. This interaction requires a domain in PLC-gamma1 that includes a partial pleckstrin homology (PH) domain-a consensus lipid-binding and protein-binding sequence. We have developed a gestalt algorithm to detect hitherto 'invisible' PH and PH-like domains, and now report that the partial PH domain of PLC-gamma1 interacts with a complementary partial PH-like domain in TRPC3 to elicit lipid binding and cell-surface expression of TRPC3. Our findings imply a far greater abundance of PH domains than previously appreciated, and suggest that intermolecular PH-like domains represent a widespread signalling mode. 相似文献
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Clark IE Dodson MW Jiang C Cao JH Huh JR Seol JH Yoo SJ Hay BA Guo M 《Nature》2006,441(7097):1162-1166
Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology. Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1; PARK6) and parkin (PARK2), which are also associated with sporadic forms of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence. So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function. Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1-parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis. 相似文献
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新型铜络合催化剂用于羰基合成碳酸二甲酯的工艺过程 总被引:2,自引:0,他引:2
针对甲醇液相氧化羰基化法合成碳酸二甲酯(DMC)工艺,研究开发了新型铜络合催化剂,对搅拌速度、反应温度、反应压力、反应时间、催化剂浓度等影响因素进行了讨论。结果表明,在搅拌速度大于750 r/min、反应压力3.5 MPa、反应温度100—110℃、反应时间4—6 h,催化剂质量浓度在每毫升MeOH为0.15 g的条件下,生成DMC的选择性大于97%,甲醇的转化率可达24%,催化剂可回收使用。 相似文献
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BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis 总被引:1,自引:0,他引:1
Danial NN Gramm CF Scorrano L Zhang CY Krauss S Ranger AM Datta SR Greenberg ME Licklider LJ Lowell BB Gygi SP Korsmeyer SJ 《Nature》2003,424(6951):952-956
Glycolysis and apoptosis are considered major but independent pathways that are critical for cell survival. The activity of BAD, a pro-apoptotic BCL-2 family member, is regulated by phosphorylation in response to growth/survival factors. Here we undertook a proteomic analysis to assess whether BAD might also participate in mitochondrial physiology. In liver mitochondria, BAD resides in a functional holoenzyme complex together with protein kinase A and protein phosphatase 1 (PP1) catalytic units, Wiskott-Aldrich family member WAVE-1 as an A kinase anchoring protein, and glucokinase (hexokinase IV). BAD is required to assemble the complex in that Bad-deficient hepatocytes lack this complex, resulting in diminished mitochondria-based glucokinase activity and blunted mitochondrial respiration in response to glucose. Glucose deprivation results in dephosphorylation of BAD, and BAD-dependent cell death. Moreover, the phosphorylation status of BAD helps regulate glucokinase activity. Mice deficient for BAD or bearing a non-phosphorylatable BAD(3SA) mutant display abnormal glucose homeostasis including profound defects in glucose tolerance. This combination of proteomics, genetics and physiology indicates an unanticipated role for BAD in integrating pathways of glucose metabolism and apoptosis. 相似文献
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NLRX1 is a regulator of mitochondrial antiviral immunity 总被引:1,自引:0,他引:1
Moore CB Bergstralh DT Duncan JA Lei Y Morrison TE Zimmermann AG Accavitti-Loper MA Madden VJ Sun L Ye Z Lich JD Heise MT Chen Z Ting JP 《Nature》2008,451(7178):573-577
The RIG-like helicase (RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection. MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus-induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti-pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses. 相似文献
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McDermott-Roe C Ye J Ahmed R Sun XM Serafín A Ware J Bottolo L Muckett P Cañas X Zhang J Rowe GC Buchan R Lu H Braithwaite A Mancini M Hauton D Martí R García-Arumí E Hubner N Jacob H Serikawa T Zidek V Papousek F Kolar F Cardona M Ruiz-Meana M García-Dorado D Comella JX Felkin LE Barton PJ Arany Z Pravenec M Petretto E Sanchis D Cook SA 《Nature》2011,478(7367):114-118
Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy. 相似文献
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孙润广 《陕西师范大学学报(自然科学版)》2003,31(1):70-75
通过X衍射晶体学法、荧光标记显微镜法、负染色体电子显微镜与单克隆抗体技术等对F1F0 ATP酶结构和功能的研究发现,在大肠杆菌、叶绿体和牛心线粒体中,F1F0 ATP酶复合体分别由8、9和16种不同的亚基组成.所有F1F0 ATP酶都有类似的结构,球状的F1和F0是由一个中心转轴和一个外围柄连接在一起.其中,中心转轴由γ和ε亚基组成,外围柄由b2(Ⅰ,Ⅱ)和δ亚基组成.在酶的催化过程中,α3β3亚基通过γ亚基与膜上的c亚基环相互作用,驱动ATP合成酶的中心转轴旋转.F1F0 ATP酶利用电化学质子梯度的能量,催化ADP(腺苷二磷酸)和Pi(无机磷酸盐)形成ATP(腺苷三磷酸). 相似文献