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CREB-binding protein sequestration by expanded polyglutamine

HUMAN MOLECULAR GENETICS 2000年第14期9卷 2197-2202页

作者： McCampbell, A Taylor, JP Taye, AA Robitschek, J Li, M Walcott, J Merry, D Chai, YH Paulson, H Sobue, G Fischbeck, KH NINDS Neurogenet Branch NIH Bethesda MD 20892 USA Nagoya Univ Sch Med Dept Neurol Showa Ku Aichi Japan Thomas Jefferson Univ Philadelphia PA 19107 USA Univ Iowa Coll Med Dept Neurol Iowa City IA 52242 USA

Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded polyglutamine tract, which likely confers a novel, toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the polyglutamine expansion, In this report we present evidence that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3, We present evidence that soluble levels of CBP are reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA, Finally, we demonstrate that over-expression of CBP rescues cells from polyglutamine-mediated toxicity in neuronal cell culture, These data support a CBP-sequestration model of polyglutamine expansion disease.

关键词： CREB结合蛋白质细胞死亡/药物作用细胞系细胞核/代谢细胞培养的 DNA结合蛋白质类真菌蛋白质类/代谢绿色荧光蛋白质类 HeLa细胞萤光素酶类/代谢发光蛋白质类/代谢 Machado-Joseph病/遗传学 Machado-Joseph病/代谢小鼠转基因肌萎缩脊髓性/遗传学肌萎缩脊髓性/代谢神经组织蛋白质类/代谢核蛋白质类/代谢肽类/代谢肽类/药理学 RNA 信使/代谢阻遏蛋白质类酿酒酵母蛋白质类阴囊/代谢四唑鎓盐类/药理学噻唑类/药理学时间因素反式激活因子类/代谢转录因子/代谢转录遗传三核苷酸重复扩增动物人类男(雄)性小鼠

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Gap junctional intercellular communication is not a major mediator in the bystander effect in photodynamic treatment of MDCK II cells

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RADIATION RESEARCH 2000年第3期154卷 331-341页

作者： Dahle, J Mikalsen, SO Rivedal, E Steen, HB Norwegian Radium Hosp Dept Biophys N-0310 Oslo Norway Norwegian Radium Hosp Inst Canc Res Dept Environm & Occupat Canc N-0310 Oslo Norway

Photodynamic treatment (PDT) of confluent MDCK II cells resulted in a noticeable clustering of dead cells, consistent with a significant bystander effect. Likewise, PDT of cells in microcolonies resulted in an overabundance of microcolonies that had responded to the treatment as a single unit, that is, in which either all or no cells were dead. Confluent MDCK II cells appeared to communicate via gap junction channels, while cells in microcolonies did not. Monte Carlo simulation models were fitted to the distributions of dead cells in confluent monolayers and in microcolonies. The simulations showed that the degree of the bystander effect was higher in microcolonies than in confluent cells, suggesting that gap junction communication may be involved in the bystander effect, However, when the gap junction hypothesis was tested by treatment of microcolonies with 30 mu M dieldrin, an inhibitor of gap junctional intercellular communication, there was no reduction of the bystander effect, indicating that this effect was not mediated by gap junctional intercellular communication, PDT influenced phosphorylation of tyrosine residues in several proteins in the cells. Protein phosphorylation is important in cellular signaling pathways and may be involved in the bystander effect, for example by influencing the mode of cell death, (C) 2000 by Radiation Research Society.

关键词：细胞间通讯/药物作用细胞死亡/药物作用细胞死亡/辐射效应细胞系/药物作用细胞系/辐射效应计算机模拟狄氏剂/药理学二血卟啉醚/药理学二血卟啉醚/辐射效应上皮细胞/药物作用上皮细胞/辐射效应缝隙接合部/药物作用缝隙接合部/生理学肾模型生物学蒙特卡罗法氧化性应激磷酰化/药物作用磷酰化/辐射效应光化学光化学疗法光敏感药/药理学蛋白质加工转译后/药物作用蛋白质加工转译后/辐射效应动物狗

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Cofactors of mitochondrial enzymes attenuate copper-induced death in vitro and in vivo

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ANNALS OF NEUROLOGY 2002年第2期52卷 195-204页

作者： Sheline, CT Choi, EH Kim-Han, JS Dugan, LL Choi, DW Washington Univ Sch Med Ctr Study Nervous Syst Injury St Louis MO 63110 USA Washington Univ Sch Med Dept Neurol St Louis MO 63110 USA

Copper toxicity contributes to neuronal death in Wilson's disease and has been speculatively linked to the pathogenesis of Alzheimer's and prion diseases. We examined copper-induced neuronal death with the goal of developing neuroprotective strategies. Copper catalyzed an increase in hydroxyl radical generation in solution, and the addition of 20muM copper for 22 hours to murine neocortical cell cultures induced a decrease in ATP levels and neuronal death without glial death. This selective neuronal death was associated with activation of caspase-3 and was reduced by free radical scavengers and Z-Val-Ala-Asp fluoromethylketone, consistent with free radical-mediated injury leading to apoptosis. Pyruvate dehydrogenase is especially vulnerable to inhibition by oxygen free radicals, and the upstream metabolites, pyruvate, phosphoenolpyruvate, and 2-phosphoglycerate were elevated in cortical cells after toxic exposure to copper. One approach to protecting pyruvate dehydrogenase from oxidative attack might be to enhance binding to cofactors. Addition of thiamine, dihydrolipoic acid, or pyruvate reduced copper-induced neuronal death. To test efficacy in vivo, we added 1% thiamine to the drinking water of Long Evans Cinnamon rats, an animal model of Wilson's disease. This thiamine therapy markedly extended life span from 6.0 +/- 1.6 months to greater than 16 months.

关键词：细胞凋亡/生理学细胞死亡/药物作用细胞死亡/生理学细胞培养的大脑皮质/细胞学铜/中毒胚胎哺乳动物自由基清除剂/代谢羟自由基/代谢长寿/药物作用神经元/药物作用神经元/代谢神经元/生理学神经保护药/药理学大鼠 Long-Evans/生理学硫胺素/药理学硫辛酸/类似物和衍生物硫辛酸/药理学动物小鼠大鼠

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Efficacy of novel Calpain inhibitors in preventing renal cell death

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期294卷 1083-1087页

作者： Harriman, JF Waters-Williams, S Chu, DL Powers, JC Schnellmann, RG Univ Arkansas Med Sci Dept Pharmacol & Toxicol Little Rock AR 72205 USA Georgia Inst Technol Sch Chem & Biochem Atlanta GA 30332 USA

Inhibitors of calpains, calcium-activated neutral proteases, protect against cell death produced by anoxia and a variety of toxicants both in vitro and in vivo. The problems with known calpain inhibitors are a lack of specificity, low membrane permeability, and/or low potency. The goal of this study was to determine the effects of seven novel dipeptide and tripeptide calpain inhibitors on calpain activity and antimycin A-induced cell death in rabbit renal proximal tubule (RPT) suspensions. We chose the compounds based on their inhibitory constants for mu- versus m-calpain, specificity of the inhibitors for calpain, and membrane permeability. Only three of the compounds inhibited calpain in RPT and were cytoprotective (Z-Leu-Phe-COOH, Z-Leu-Abu-CONH-CH2-CH(OH)-Ph, and Z-Leu-Phe-CONH-Et). Interestingly, Z-Leu-Phe-COOEt, Z-Leu-Abu-CONH-CH2-CH(OH)-C6F5, and Z-Leu-Abu-CONH-CH2-2-quinolinyl were greater than 60% cytoprotective but did not inhibit calpain in RPT. Z-Leu-Abu-CONH(CH2)(3)-morpholine was neither cytoprotective nor inhibited calpain. Although these results suggest that six of the seven peptide calpain inhibitors are cell permeable, only three of them inhibited calpain activity in RPT and were cytoprotective. Their ability to inhibit calpain or produce cytoprotection did not correlate with their ability to selectively inhibit purified mu- or m-calpain. Thus it remains to be determined whether they inhibit mu-calpain, m-calpain, or both in RPT. These results also suggest that inhibition of other protease(s) in addition to calpains may be responsible for the cytoprotective actions of some compounds.

关键词：抗霉素A 卡配因/拮抗剂和抑制剂细胞死亡/药物作用细胞膜通透性二肽类/药理学酶抑制剂/药理学同工酶类/拮抗剂和抑制剂肾小管近端/细胞学肾小管近端/药物作用肾小管近端/酶学寡肽类/药理学动物女(雌)性兔

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Structure-activity relationship study of Asiatic acid derivatives against beta amyloid (Aβ)-induced neurotoxicity (vol 10, pg 119, 2000)

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第13期10卷 1495-1495页

作者： Jew, SS Yoo, CH Lim, DY Kim, H Mook-Jung, I Jung, MW Choi, H Jung, YH Kim, H Park, HG Seoul Natl Univ Coll Pharm Seoul 151742 South Korea Ajou Univ Sch Med Brain Dis Res Ctr Suwon 441749 South Korea Ajou Univ Sch Med Inst Med Sci Suwon 441749 South Korea Dong Kook Pharmaceut Co Ltd Cent Res Inst Choong Cheong Book Do South Korea Sungkyunkwan Univ Coll Pharm Suwon 440746 South Korea Sookmyung Woman Univ Coll Pharm Seoul South Korea

8 Semi-synthetic derivatives of asiatic acid were prepared and their protective effect against Aβ-induced neurotoxicity was evaluated. Among them, asiatic acid (2), and 4, 16 showed 97, 92 and 87% of protective effec... 详细信息

关键词：阿尔茨海默病/药物疗法淀粉样β肽类/拮抗剂和抑制剂淀粉样β肽类/药理学细胞死亡/药物作用细胞系分子结构神经保护药/化学合成神经保护药/药理学五环三萜类肽碎片/拮抗剂和抑制剂肽碎片/药理学植物药用/化学构效关系三萜类/化学三萜类/药理学人类

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Effects of n-3 fatty acids on growth and survival of J774 macrophages

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PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS 2000年第3期62卷 201-207页

作者： Fyfe, DJ Abbey, M CSIRO Hlth & Nutr Adelaide SA 5000 Australia

To further understand potential mechanisms underlying the protective effects of eicosapentanoic acid (EPA) against atherosclerosis, J774 macrophages were used to explore cellular responses to growth in the presence of PUFA in vitro. Clonogenic assays indicated that 15 mu g/ml of EPA killed over 90% of J774 populations. Docosapentaenoic acid (DPA) was more cytotoxic than either EPA or docosahexaenoic acid (DHA). EPA was shown to be elongated to DPA. Cytotoxicity induced by EPA was not inhibited by the presence of alpha-tocopherol (a-toc) in the medium. Immunological screening for caspase enzymes and microscopic examination indicated that apoptosis was not the major cause of cell death. Proliferation assays demonstrated that total cell numbers of EPA-treated cells were not significantly different to control cells. Increasing does of EPA were correlated with increasing levels of intracellular malondialdehyde (MDA). These observations suggest that EPA may influence the growth parameters of macrophages whilst inducing moderately elevated levels of oxidative stress. (C) 2000 Harcourt Publishers Ltd.

关键词：细胞死亡/药物作用细胞分裂/药物作用细胞系细胞存活/药物作用色谱法气相色谱法高压液相脂肪酸类/分析脂肪酸类 ω3/药理学巨噬细胞/细胞学巨噬细胞/药物作用巨噬细胞/代谢丙二醛/代谢动物小鼠

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Antimitotic diterpenes from Erythropodium caribaeorum test pharmacophore models for microtubule stabilization

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ORGANIC LETTERS 2000年第3期2卷 257-260页

作者： Cinel, B Roberge, M Behrisch, H van Ofwegen, LP Castro, CB Andersen, RJ Univ British Columbia Dept Chem EOS Vancouver BC V6T 1Z1 Canada Univ British Columbia Dept Radiol EOS Vancouver BC V6T 1Z1 Canada Univ British Columbia Dept Biochem & Mol Biol Vancouver BC V6T 1Z3 Canada Natl Museum Nat Hist Leiden Netherlands Museu Nacl Rio De Janeiro Brazil

[GRAPHICS] Six new antimitotic diterpenes, 2-7, have been isolated from the Caribbean octocoral Erythropodium caribaeorum, Structural variations encountered in this group of natural products test recently proposed pha... 详细信息

关键词：生物碱类/化学生物碱类/分离和提纯生物碱类/药理学抗肿瘤药/化学抗肿瘤药/分离和提纯细胞周期/药物作用细胞死亡/药物作用腔肠动物门/化学二萜类/化学二萜类/分离和提纯二萜类/药理学半数抑制浓度微管/化学模型分子构效关系动物

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IL-1 rescues scleroderma myofibroblasts from serum-starvation-induced cell death

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第1期255卷 129-132页

作者： Kirk, TZ Mayes, MD Wayne State Univ Sch Med Div Rheumatol Detroit MI 48201 USA

Normal senescent adult human fibroblasts are relatively insensitive to the effects of serum deprivation in culture, In contrast, the myofibroblast phenotype, which is predominant in scleroderma-affected skin and cultured fibroblasts from scleroderma-affected skin, shows signs of deterioration within 3 days of serum starvation. The addition of IL-1 (5 ng/ml) prevents this deterioration. We propose that IL-1 is a factor promoting myofibroblast longevity with consequent fibrosis in scleroderma skin. (C) 1999 Academic Press.

关键词：细胞死亡/药物作用细胞存活/药物作用细胞培养的成纤维细胞/病理学白细胞介素1/药理学硬皮病局部性/病理学成年人人类

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The mode of cell death induced by photodynamic treatment depends on cell density

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PHOTOCHEMISTRY AND PHOTOBIOLOGY 1999年第3期70卷 363-367页

作者： Dahle, J Steen, HB Moan, J Norwegian Radium Hosp Dept Biophys N-0310 Oslo Norway

Madison Darby canine kidney II (MDCK II) cells were seeded out at two different densities and incubated with 125 IJ mu g/mL of the photosensitizer meso-tetra(4-sulfonatophenyl)porphine (TPPS4) for 18 h, washed and irradiated with blue light. Four hours later the cells were studied by fluorescence microscopy. Apoptotic cells were detected by virtue of the distinct condensation and fragmentation of chromatin, and necrotic cells were detected by uptake of propidium iodide. In addition apoptosis was measured by the TdT assay. The fraction of apoptotic cells and the fraction of necrotic cells were determined for both cell densities at various levels of survival. With <55% total cell death the apoptotic fraction was significantly higher for cells in confluent monolayers than for cells growing in microcolonies at equitoxic doses. Confluent cells were 2.9 times more sensitive than cells in microcolonies partly due to a 1.5 times higher uptake of TPPS4 in monolayer cells. The difference in mode of cell death for the different cell densities was not related to any observable difference in subcellular localization pattern of TPPS4 at equitoxic doses of photodynamic treatment.

关键词：细胞凋亡/药物作用细胞凋亡/生理学细胞计数细胞死亡/药物作用细胞死亡/生理学细胞系肾/细胞学肾/药物作用光化学疗法/方法卟啉类/毒性辐射增敏药/毒性动物狗

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A low voltage-activated Ca²⁺ current mediates cytokine-induced pancreatic β-cell death

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ENDOCRINOLOGY 1999年第3期140卷 1200-1204页

作者： Wang, L Bhattacharjee, A Zuo, Z Hu, FQ Honkanen, RE Berggren, PO Li, M Univ S Alabama Coll Med Dept Pharmacol Mobile AL 36688 USA Univ S Alabama Coll Med Dept Biochem Mobile AL 36688 USA Karolinska Inst Dept Mol Med Rolf Luft Ctr Diabet Res S-17176 Stockholm Sweden

Insulin-dependent diabetes mellitus is characterized by the selective destruction of pancreatic beta-cells. Chronic treatment with cytokines induced a low voltage-activated (LVA) Ca2+ current in mouse beta-cells. The concomitant increase in the basal cytoplasmic free Ca2+ concentration ([Ca2+](i)) was associated with DNA fragmentation and cell death. Antagonists of LVA Ca2+ channels prevented this elevation of basal [Ca2+](i) and DNA fragmentation and reduced the percentage of cell death. Exposure to cytokines did not affect the profile of Ca2+ currents or basal [Ca2+](i) in glucagon-secreting alpha-cells. An increased Ca2+ signal through LVA Ca2+ channels may thus be a key feature in cytokine-induced beta-cell destruction.

关键词：钙通道/生理学细胞死亡/药物作用细胞系细胞因子类/药理学 DNA碎片裂干扰素Ⅱ型/药理学白细胞介素1/药理学胰岛/药物作用胰岛/病理学膜片钳术肿瘤坏死因子α/药理学动物小鼠

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