共查询到20条相似文献,搜索用时 31 毫秒
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The cellular biological function of the ubiquitin-proteasome pathway as a major intracellular protein degradation pathway, and as an important modulator for the regulation of many fundamental cellular processes has been greatly appreciated over the last decade. The critical role of the ubiquitin-proteasome pathway in viral pathogenesis has become increasingly apparent. Many viruses have been reported to evolve different strategies to utilize the ubiquitin-proteasome pathway for their own benefits. Here, we review the general background and function of the ubiquitin-proteasome pathway, summarize our current understanding of how viruses use this pathway to target cellular proteins, and finally, discuss the roles of this pathway in enteroviral infection, and the potential therapeutic application of proteasome inhibition in myocarditis. 相似文献
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Araya J Maruyama M Inoue A Fujita T Kawahara J Sassa K Hayashi R Kawagishi Y Yamashita N Sugiyama E Kobayashi M 《American journal of physiology. Lung cellular and molecular physiology》2002,283(4):L849-L858
Inhalation of particulate cobalt has been known to induce interstitial lung disease. There is growing evidence that apoptosis plays a crucial role in physiological and pathological settings and that the ubiquitin-proteasome system is involved in the regulation of apoptosis. Cadmium, the same transitional heavy metal as cobalt, has been reported to accumulate ubiquitinated proteins in neuronal cells. On the basis of these findings, we hypothesized that cobalt would induce apoptosis in the lung by disturbance of the ubiquitin-proteasome pathway. To evaluate this, we exposed U-937 cells and human alveolar macrophages (AMs) to cobalt chloride (CoCl(2)) and examined their apoptosis by DNA fragmentation assay, 4',6-diamidino-2'-phenylindol dihydrochloride staining, and Western blot analysis. CoCl(2) induced apoptosis and accumulated ubiquitinated proteins. Exposure to CoCl(2) inhibited proteasome activity in U-937 cells. Cobalt-induced apoptosis was mediated via mitochondrial pathway because CoCl(2) released cytochrome c from mitochondria. These results suggest that cobalt-induced apoptosis of AMs may be one of the mechanisms for cobalt-induced lung injury and that the accumulation of ubiquitinated proteins might be involved in this apoptotic process. 相似文献
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S Gupta 《Life sciences》2001,69(25-26):2957-2964
In almost all multicellular organisms, cell suicide or apoptosis appears to play an important role in the maintenance of cellular homeostasis. Apoptosis is tightly regulated by a set of genes that either promote apoptosis or promote cell survival. Although a number of stimuli appear to trigger the process of apoptosis, there are two major signaling pathways of apoptosis; the death receptor pathway and the death receptor-independent or mitochondrial pathway. There is evidence to suggest that, under certain conditions and in some cell types; these two pathways may cross talk. During the past 5 years, rapid progress has been made in understanding the molecular basis of apoptosis. In this brief review, I will summarize the various molecular steps of apoptosis. 相似文献
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Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) RTA is an important protein involved in the induction of KSHV lytic replication from latency through activation of the lytic cascade. A number of cellular and viral proteins, including K-RBP, have been found to repress RTA-mediated transactivation and KSHV lytic replication. However, it is unclear as to how RTA overcomes the suppression during lytic reactivation. In this study, we found that RTA can induce K-RBP degradation through the ubiquitin-proteasome pathway and that two regions in RTA are responsible. Moreover, we found that RTA can promote the degradation of several other RTA repressors. RTA mutants that are defective in inducing K-RBP degradation cannot activate RTA responsive promoter as efficiently as wild-type RTA. Interference of the ubiquitin-proteasome pathway affected RTA-mediated transactivation and KSHV reactivation from latency. Our results suggest that KSHV RTA can stimulate the turnover of repressors to modulate viral reactivation. Since herpes simplex virus type 1 transactivator ICP0 and human cytomegalovirus transactivator pp71 also stimulate the degradation of cellular silencers, it is possible that the promotion of silencer degradation by viral transactivators may be a common mechanism for regulating the lytic replication of herpesviruses. 相似文献
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The sequestosome 1/p62 protein has been implicated in the regulation of a multitude of cellular processes such as NF-kB signaling,NRF2-driven oxidative stress response,protein turnover through the ubiq... 相似文献
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Receptor-interacting protein kinase 3 (RIPK3) is a serine/threonine kinase with essential function in necroptosis. The activity of RIPK3 is controlled by phosphorylation. Once activated, RIPK3 phosphorylates and activates the downstream effector mixed lineage kinase domain-like (MLKL) to induce necroptosis. In certain situations, RIPK3 has also been shown to promote apoptosis or cytokine expression in a necroptosis and kinase-independent manner. The ubiquitin-proteasome system is the major pathway for selective degradation of cellular proteins and thus has a critical role in many cellular processes such as cell survival and cell death. Clinically, proteasome inhibition has shown promise as an anti-cancer agent. Here we show that the proteasome inhibitors MG132 and bortezomib activate the RIPK3-MLKL necroptotic pathway in mouse fibroblasts as well as human leukemia cells. Unlike necroptosis induced by classical TNF-like cytokines, necroptosis induced by proteasome inhibitors does not require caspase inhibition. However, an intact RIP homotypic interaction motif (RHIM) is essential. Surprisingly, when recruitment of MLKL to RIPK3 is restricted, proteasome inhibitors induced RIPK3-dependent apoptosis. Proteasome inhibition led to accumulation of K48-linked ubiquitinated RIPK3, which was partially reduced when Lys-264 was mutated. Taken together, these results reveal the ubiquitin-proteasome system as a novel regulatory mechanism for RIPK3-dependent necroptosis. 相似文献
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The ubiquitin-proteasome pathway plays a critical role in the degradation of several proteins involved in the cell cycle. Dysregulation of this pathway leads to inhibition of cellular proliferation and the induction of apoptosis. Ubiquitination and its downstream consequences have been investigated intensively as targets for the development of drugs for tumour therapy. Here we have investigated the mechanism of apoptosis induced by the proteasome inhibitors MG-132, lactacystin and calpain inhibitor I (ALLN), in the HEK 293 cell line and the ovarian cancer cell lines SKOV3 and OVCAR3. We have found strong caspase-3-like and caspase-6-like activation upon treatment of HEK 293 cells with MG-132. Using a tricistronic expression vector based on a tetracycline-responsive system we generated stable SKOV3 nd OVCAR3 cell lines with inducible expression of pro-caspase-3. Induction of pro-caspase-3 expression in normally growing cells does not induce apoptosis. However, in the presence of the proteasome inhibitors MG-132, lactacystin or ALLN we found that cells overexpressing pro-caspase-3 are rapidly targeted for apoptosis. Our results demonstrate that pro-caspase-3 can sensitise ovarian cancer cells to proteasome inhibitor-induced apoptosis, and a combination of these approaches might be exploited for therapy of ovarian and other cancers. 相似文献
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Beverly LJ 《Journal of cellular biochemistry》2012,113(1):3-12
All aspects of cellular biology affect the process of regulated cell death, or apoptosis, and disruption of this process is a causative event in many diseases. Therefore, a comprehensive understanding of all pathways that regulate apoptosis would increase our knowledge of basic cellular functions, as well as the etiologies of many diseases. In turn, we may be able to use this knowledge to better treat patients with diseases, including cancer. Although the basic signaling pathway that regulates apoptosis has been known for over 10 years, we still have much to learn about the upstream signaling components that can directly regulate the core apoptosis machinery. The focus of this review will be to direct attention to non-canonical regulators of the BCL2-family of proteins, especially our void of understanding of such interactions, and the controversy that surrounds some such interactions. 相似文献
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泛素-蛋白水解酶复合体通路与病毒侵染 总被引:5,自引:0,他引:5
泛素-蛋白水解酶复合体通路(Ubiquitinproteasome pathway, UPP)是细胞内依赖于ATP、非溶酶体途径的蛋白质降解通路,广泛参与包括细胞周期调控、细胞凋亡、信号转导、转录调控、免疫应答及抗原呈递等多种机体代谢活动。UPP在病毒侵染中作用的研究仍处于起步阶段。已发现,昆虫病毒和非洲猪瘟病毒分别是迄今发现唯一编码泛素和泛素连接酶的病毒。最近,大量的研究表明,病毒利用宿主细胞的UPP逃避免疫系统监控、促进病毒复制以及进行病毒粒子的组装和释放。 相似文献
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Guodong ZhangJing Liu Ye ZhangJinglei Qu Ling XuHuachuan Zheng Yunpeng Liu Xiujuan Qu 《FEBS letters》2012,586(19):3104-3110
Various molecular mechanisms are involved in the efficacy of arsenic trioxide (ATO) against malignant hematologic and some solid tumors. FLICE-like inhibitory protein (FLIP) is an inhibitor of apoptosis mediated by death receptors. In this study, we identified a new link between the down-regulation of cellular FLIPL and ATO-induced autophagy. ATO induced the degradation of FLIPL in K562 and MGC803 cells, which was mediated by the ubiquitin-proteasome pathway. Moreover, the casitas B-lineage lymphoma-b (Cbl-b) was involved in this process, which interacted with FLIPL and promoted proteasomal degradation of FLIPL. Our findings lead to a better understanding of the mechanism of action of ATO, and suggest that a novel signaling pathway is required for ATO-induced autophagy in K562 and MGC803 cells.
Structured summary of protein interactions
FLIP-Lphysically interacts with CBL-B by anti bait coimmunoprecipitation (View interaction) 相似文献14.
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Chanvorachote P Nimmannit U Wang L Stehlik C Lu B Azad N Rojanasakul Y 《The Journal of biological chemistry》2005,280(51):42044-42050
Stimulation of cell surface Fas (CD95) results in recruitment of cytoplasmic proteins and activation of caspase-8, which in turn activates downstream effector caspases leading to programmed cell death. Nitric oxide (NO) plays a key role in the regulation of apoptosis, but its role in Fas-induced cell death and the underlying mechanism are largely unknown. Here we show that stimulation of the Fas receptor by its ligand (FasL) results in rapid generation of NO and concomitant decrease in cellular FLICE inhibitory protein (FLIP) expression without significant effect on Fas and Fas-associated death domain (FADD) adapter protein levels. FLIP down-regulation as well as caspase-8 activation and apoptosis induced by FasL were all inhibited by the NO-liberating agent sodium nitroprusside and dipropylenetriamine NONOate, whereas the NO synthase inhibitor aminoguanidine and NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO) had opposite effects, indicating an anti-apoptotic role of NO in the Fas signaling process. FasL-induced down-regulation of FLIP is mediated by a ubiquitin-proteasome pathway that is negatively regulated by NO. S-nitrosylation of FLIP is an important mechanism rendering FLIP resistant to ubiquitination and proteasomal degradation by FasL. Deletion analysis shows that the caspase-like domain of FLIP is a key target for S-nitrosylation by NO, and mutations of its cysteine 254 and cysteine 259 residues completely inhibit S-nitrosylation, leading to increased ubiquitination and proteasomal degradation of FLIP. These findings indicate a novel pathway for NO regulation of FLIP that provides a key mechanism for apoptosis regulation and a potential new target for intervention in death receptor-associated diseases. 相似文献
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Degradation of Id proteins by the ubiquitin-proteasome pathway. 总被引:11,自引:0,他引:11
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细胞凋亡是一种程序化的细胞死亡方式,其信号传导通路分为外源性和内源性两条主要途径,线粒体在内源性细胞凋亡途径中扮演着重要的角色.研究表明,运动可通过调节线粒体介导骨骼肌细胞凋亡的进程,而运动调节线粒体介导骨骼肌细胞凋亡信号通路影响机体细胞生物进程的机制仍有待研究.该文主要阐述了线粒体介导细胞凋亡信号传导通路及运动对其的... 相似文献
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The ubiquitin-proteasome system 总被引:10,自引:0,他引:10
The 2004 Nobel Prize in chemistry for the discovery of protein ubiquitination has led to the recognition of cellular proteolysis
as a central area of research in biology. Eukaryotic proteins targeted for degradation by this pathway are first ‘tagged’
by multimers of a protein known as ubiquitin and are later proteolyzed by a giant enzyme known as the proteasome. This article
recounts the key observations that led to the discovery of ubiquitin-proteasome system (UPS). In addition, different aspects
of proteasome biology are highlighted. Finally, some key roles of the UPS in different areas of biology and the use of inhibitors
of this pathway as possible drug targets are discussed. 相似文献