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Lee SH Kalejta RF Kerry J Semmes OJ O'Connor CM Khan Z Garcia BA Shenk T Murphy E 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(24):9575-9580
Cell proteins can restrict the replication of viruses. Here, we identify the cellular BclAF1 protein as a human cytomegalovirus restriction factor and describe two independent mechanisms the virus uses to decrease its steady-state levels. Immediately following infection, the viral pp71 and UL35 proteins, which are delivered to cells within virions, direct the proteasomal degradation of BclAF1. Although BclAF1 reaccumulates through the middle stages of infection, it is subsequently down-regulated at late times by miR-UL112-1, a virus-encoded microRNA. In the absence of BclAF1 neutralization, viral gene expression and replication are inhibited. These data identify two temporally and mechanistically distinct functions used by human cytomegalovirus to down-regulate a cellular antiviral protein. 相似文献
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Myeloma is a malignancy of the antibody-producing plasma cells and, as such, these cells synthesize large quantities of unfolded or misfolded immunoglobulin. The build-up of excess protein triggers a number of downstream signal transduction cascades, including endoplasmic reticulum stress and autophagy. As a result, myeloma cells are uniquely reliant on these and other protein handling pathways for their survival. Strategies aimed at targeting this vulnerability have proved successful with the proteasome inhibitor, bortezomib, already licensed for clinical use. In addition to the proteasome, various other points within the protein handling pathways are also the subject of drug discovery projects, with some already progressing into clinical trials. These include compounds directed against heat shock proteins, the unfolded protein response and pathways both upstream and downstream of the proteasome. More recently, the role of autophagy has been recognized in myeloma. In this review, we discuss the various pathways used by myeloma cells for survival, with particular emphasis on the emerging role and conundrum of autophagy, as well as highlighting pre-clinical research on novel inhibitors targeting protein handling pathways. 相似文献
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目的 利用Crispr/Cas9系统建立蛋白酶体成熟蛋白(proteasome maturation protein,POMP)基因组原位荧光报告系统.方法 构建POMP-2A-mCherry-T载体并转染HEK293(human embryonic kdiney 293 cell)细胞;流式细胞仪分选获取mCherry阴阳性细胞;实时荧光定量PCR(real-time fluorescent quantitative PCR)检测mCherry阴阳性细胞中POMP基因转录水平表达差异;Western blot检测mCherry阴阳性细胞中POMP蛋白表达差异以及Huh7细胞中JNK1/JNK2磷酸化水平;蛋白酶体活性试剂盒检测mCherry阴阳性细胞中蛋白酶体活性差异.结果 mCherry阳性细胞POMP蛋白表达水平比mCherry阴性细胞高1.3倍(P<0.01),但其基因转录水平差异并不显著(P>0.05);同时mCherry阴性细胞中泛素化水平比mCherry阳性细胞高1.2倍(P<0.01);另外mCherry阳性细胞中蛋白酶体活性也显著高于阴性细胞(P<0.01);低表达POMP的Huh7细胞中,JNK1和JNK2的磷酸化水平分别升高1.5倍和1.4倍(P<0.01).结论 成功构建POMP荧光报告系统;将该系统用于Huh7细胞,发现POMP可改变JNK1、JNK2磷酸化水平,其可能通过JNK信号通路来影响细胞的增殖以及凋亡. 相似文献
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BACKGROUND: Previously we showed that the human sperm proteasome plays significant roles during mammalian fertilization. Here we studied the effect of fibronectin (Fn), an extracellular matrix protein present in the cumulus oophorus of the oocyte, on proteasome activity, acrosome reaction, intracellular calcium concentration ([Ca(2+)](i)) and protein tyrosine phosphorylation of human sperm. METHODS: Aliquots of motile sperm were incubated for 15 min (T0), 5 h (T5) and 18 h (T18), at 37 degrees C, 5% CO(2) and 95% air with Fn (0-100 microg/ml). The chymotrypsin- and trypsin-like activity of the proteasome was measured using the fluorogenic substrates, Suc-Leu-Leu-Val-Tyr-AMC and Boc-Gln-Ala-Arg-AMC, respectively. At T18, sperm aliquots were incubated for 15 min with Fn and/or progesterone in the presence or absence of epoxomicin (a proteasome inhibitor). The percentage of viable acrosome reacted sperm was evaluated using the Fluorescein isothiocyanate (FITC)-labeled Pisum sativum agglutinin. Tyrosine phosphorylation was evaluated by western blot and [Ca(2+)](i) using fura 2. RESULTS: Fn stimulated both enzymatic activities of the proteasome and the acrosome reaction of human sperm. Progesterone enhanced and epoxomicin drastically inhibited the effect of Fn. Fn treatment also increased the [Ca(2+)](i). Western blot analysis revealed that Fn increased tyrosine protein phosphorylation and that some proteasome subunits became tyrosine phosphorylated upon Fn treatment. CONCLUSIONS: These results suggest that Fn activates the proteasome and induces the acrosome reaction in human sperm. This effect may involve binding with specific receptors (integrins) on the sperm surface and the activation of tyrosine kinases. 相似文献
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Background
Even after several novel therapeutic approaches, the number of people with diabetic nephropathy (DN) still continues to increase globally, this suggest to find novel therapeutic strategies to prevent it completely. Recent reports, are indicating the ubiquitin proteasome system alterations in DN. Recently, we also showed that, histone H2AK119 mono-ubiquitination (H2AK119-Ub) found to regulate Set7, a key epigenetic enzyme in the development of renal fibrosis under type 1 diabetic condition. Hence, we aimed to study the role of a known 20 s proteasome inhibitor Aspirin, on histone ubiquitination in the progression of DN.Methods
Male Wistar rats were rendered diabetic using a single dose of Streptozotocin (55 mg kg?1, ip). After 4 weeks, diabetic animals were grouped into respective groups and the drug, aspirin, low dose (25 mg kg?1 day?1), high dose (50 mg kg?1 day?1) was administered through po route. At the end of the study, kidneys from all the groups were collected and processed separately for glomerular isolation, protein isolation, and for histopathological studies.Results
Aspirin administration, reduced the protein expression of Mysm1, increased the protein expression of H2AK119-Ub and thereby reduced the Set7 protein expression in glomeruli isolated from diabetic animals and prevented renal fibrosis.Conclusions
In conclusion, our results are clearly indicating that, aspirin prevents renal fibrosis in diabetic animals through decreasing the expression of Mysm1, increasing the expression of H2AK119-Ub and thereby decreasing the protein expression of Set7, which is a novel mechanism. Moreover, this mechanism may lay down a novel strategy to prevent DN completely in future. 相似文献40.
阻断泛素-蛋白酶体通路对胃癌细胞增殖和凋亡的影响 总被引:6,自引:0,他引:6
目的 研究阻断泛素 蛋白酶体通路对胃癌细胞增殖的抑制作用及其机制。方法 将泛素 蛋白酶体通路特异性阻断剂MG 132加入胃癌细胞株SGC 790 1,四甲基偶氮唑蓝 (MTT)法测定细胞抑制效应 ,流式细胞仪 (FCM )检测细胞周期及凋亡 ,DNA片段分析进一步证实凋亡的存在 ,TRAPPCR ELISA法检测端粒酶活性 ,免疫细胞化学检测 p2 7kip1的表达。 结果 MG 132对SGC 790 1细胞有显著抑制作用 ;FCM显示对照组胃癌细胞G0 /G1期比例为 (46 .3± 4 .1) % ,MG 132作用后为 (72 .1± 5 .0 ) % ,较对照组增加 (P <0 .0 1) ,并有明显的亚二倍体凋亡峰 ;细胞DNA抽提电泳后发现特征性凋亡梯状条带 ,TRAPPCR ELISA法检测示MG 132作用胃癌细胞 2 4、4 8、72、96h时A值分别为 0 .197± 0 .0 0 7、0 .0 81± 0 .0 0 5、0 .0 74± 0 .0 0 4、0 .0 6 3± 0 .0 0 2 ,对照组A值分别为 1.80 1± 0 .0 4 8、1.887± 0 .0 72、2 .0 4 7± 0 .0 85、2 .131± 0 .0 76 ;端粒酶活性显著受抑制 (P <0 .0 1) ;p2 7kip1在胃癌细胞中为胞质表达 ,经MG 132作用后 ,胞质、胞核均有表达。结论 MG 132能显著抑制胃癌细胞株SGC 790 1的增殖、诱导其凋亡 ,其机制是增强 p2 7kip1表达 ,使细胞产生G1期阻滞 ,并抑制端粒酶活性。 相似文献