Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream kinase MK2, regulates the stability of many proinflammatory mRNAs that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating the expression or activity of ARE-binding proteins that regulate mRNA turnover. MK2 phosphorylates the ARE-binding and mRNA-destabilizing protein tristetraprolin (TTP) at serines 52 and 178. Here we show that the p38 MAPK pathway regulates the subcellular localization and stability of TTP protein. A p38 MAPK inhibitor causes rapid dephosphorylation of TTP, relocalization from the cytoplasm to the nucleus, and degradation by the 20S/26S proteasome. Hence, continuous activity of the p38 MAPK pathway is required to maintain the phosphorylation status, cytoplasmic localization, and stability of TTP protein. The regulation of both subcellular localization and protein stability is dependent on MK2 and on the integrity of serines 52 and 178. Furthermore, the extracellular signal-regulated kinase (ERK) pathway synergizes with the p38 MAPK pathway to regulate both stability and localization of TTP. This effect is independent of kinases that are known to be synergistically activated by ERK and p38 MAPK. We present a model for the actions of TTP and the p38 MAPK pathway during distinct phases of the inflammatory response.
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PMID:Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. 1650 15

We demonstrate here for the first time novel positive and negative effects of the FLICE-like inhibitory protein (FLIP) on human prostate cancer cell survival. A proteaosome inhibitor, MG132, mediated cell cycle arrest at G2/M and apoptosis through p38 activation. Interestingly, FLIP was stabilized by MG132 and interacted with Raf-1, resulting in enhancement of p38 signals and cytotoxicity. In contrast, overexpression of FLIP inhibited ubiquitylation and proteasomal degradation of beta-catenin, resulting in increase of the target gene cyclin D1, colony formation and invasive activity. Immunohistochemical analysis and in vitro experiments in primary culture showed FLIP to be overexpressed, statistically associated with expression of beta-catenin/cyclin D1 in metastatic cells, the FLIP/beta-catenin/cyclin D1 signals contributing to colony formation and invasion, which were canceled by FLIP knock down. In contrast, MG132-induced cytotoxicity including apoptosis was strongly inhibited by reduction of FLIP. Taken together, the results indicate that FLIP plays an important role in development of metastatic prostate cancer by inhibiting proteasomal degradation of beta-catenin, whereas it is mainly involved in proteasome inhibitior-mediated cell cycle arrest and apoptosis through activating the Raf-1/p38 pathway. Furthermore, proteasome inhibitors may be effective drugs for advanced prostate cancers overexpressing FLIP.
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PMID:Specific positive and negative effects of FLIP on cell survival in human prostate cancer. 1653 61

Mutations in the parkin gene, encoding an E3 ubiquitin-protein ligase, are a frequent cause of autosomal recessive parkinsonism and are also involved in sporadic Parkinson's disease. Loss of Parkin function is thought to compromise the polyubiquitylation and proteasomal degradation of specific substrates, leading to their deleterious accumulation. Several studies have analyzed the effects of parkin gene mutations on the biochemical properties of the protein. However, the absence of a cell-free system for studying intrinsic Parkin activity has limited the interpretation of these studies. Here we describe the biochemical characterization of Parkin and 10 pathogenic variants carrying amino-acid substitutions throughout the sequence. Mutations in the RING fingers or the ubiquitin-like domain decreased the solubility of the protein in detergent and increased its tendency to form visible aggregates. None of the mutations studied compromised the binding of Parkin to a series of known protein partners/substrates. Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely in vitro ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this in vitro assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitin-protein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multimonoubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function.
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PMID:Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. 1671

Our previous work demonstrated that the proteasome is central to most of genes induced by lipopolysaccharide. In this study, we evaluated the role of the proteasome in response to two other microbial stimuli, CpG DNA (bacterial DNA) and peptidoglycan (PG), by measuring the effect of proteasome inhibition on cytokine secretion, induction of inflammatory gene expression, and activation of mitogen-activated protein kinases (MAPK) in murine macrophages. Pretreatment of macrophage cultures with lactacystin, a well-established proteasome inhibitor, significantly repressed tumor necrosis factor alpha secretion and tumor necrosis factor alpha and interleukin 1 beta gene expression, blocked the degradation of IkappaB, and dysregulated phosphorylation of MAPK induced by CpG DNA or PG. With respect to MAPK, lactacystin blocked expression of PG- or CpG-induced phosphorylated ERK1 and ERK2 and increased expression of phosphorylated c-Jun amino-terminal kinase but had no significant effect on phosphorylated p38. Increased expression of phoshorylated c-Jun amino-terminal kinase did not lead to an increase in AP-1 binding activity. Collectively, these data strongly support the conclusion that the proteasome is a key regulator of the CpG DNA- and PG-induced signaling pathways.
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PMID:Proteasome-mediated regulation of CpG DNA- and peptidoglycan-induced cytokines, inflammatory genes, and mitogen-activated protein kinase activation. 1672 Dec 67

All-trans-retinoic acid and the tumor suppressor promyelocytic leukemia protein (PML) are potent regulators of the growth of cancer cells. This study investigates the individual and combined effects of PML, when overexpressed by the recombinant PML adenovirus, and all-trans-retinoic acid on the proliferation of human estrogen-receptor negative SKBR-3 and estrogen-receptor positive MCF-7 breast cancer cell lines. All-trans-retinoic acid caused a significant degree of cell death in SKBR-3 cells and MCF-7 cells, and PML elicited a similar incidence of or slightly more cell death in MCF-7 cells. Dual-treated cells displayed significantly less cell death than did single-treated cells in the same cell line. We concluded that PML and all-trans-retinoic acid cause cell death by different pathways: PML activates ERK1/2, p38 MAPK, and p21; arrests the cell cycle; and later causes cell death; and all-trans-retinoic acid activates proteasome function, caspase cleavage, and apoptosis. The combined use of all-trans-retinoic acid and PML gene therapy may not be the best treatment for patients with cancer, because the ubiquitinylation of PML and its subsequent proteasome-dependent degradation by retinoic acids occur before overexpressed PML exhibits tumor-suppressive activity.
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PMID:Retinoic acid attenuates promyelocytic leukemia protein-induced cell death in breast cancer cells by activation of the ubiquitin-proteasome pathway. 1674 Mar 59

Proteasome inhibitors represent a novel class of anti-tumor agents that have clinical efficacy against hematologic malignancies, but single-agent activity against solid tumors such as breast cancer has been disappointing, perhaps due to activation of anti-apoptotic survival signals. To evaluate a possible role for the p38 mitogen-activated protein kinase (MAPK), A1N4-myc human mammary epithelial, and BT-474 and MDA-MB-231 breast carcinoma cells, were studied. Exposure of these lines to pharmacologic p38 blockade enhanced proteasome inhibitor-mediated apoptosis, as did overexpression of dominant negative (DN)-p38-alpha and -beta-MAPK isoforms. Inhibition of p38 resulted in suppression of induction of anti-apoptotic MAPK phosphatase (MKP)-1, in association with enhanced activation of the pro-apoptotic c-Jun-N-terminal kinase (JNK). Moreover, infection of cells treated with a proteasome inhibitor/p38 inhibitor combination with Adenovirus (Ad) inducing over-expression of MKP-1 suppressed apoptosis compared with controls. Further targets of p38 MAPK were also studied, and proteasome inhibition activated phosphorylation of MAPK-activated protein kinase-2, heat shock protein (HSP)-27, and the AKT8 virus oncogene cellular homolog (Akt). Inhibition of p38 MAPK resulted in decreased phospho-HSP-27 and phospho-Akt, while down-regulation of HSP-27 with a small interfering RNA decreased phosphorylation of Akt, directly linking activation of p38 to Akt. Finally, inhibition of Akt with phosphatidylinositol-3-kinase inhibitors increased apoptosis, as did over-expression of DN-Akt. These studies support the hypothesis that proteasome inhibitors activate an anti-apoptotic survival program through p38 MAPK that involves MKP-1 and Akt. Further, they suggest that strategies targeting MKP-1 and Akt could enhance the anti-tumor efficacy of proteasome inhibitors against breast cancer.
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PMID:Proteasome inhibitors induce a p38 mitogen-activated protein kinase (MAPK)-dependent anti-apoptotic program involving MAPK phosphatase-1 and Akt in models of breast cancer. 1680 78

To investigate the upstream effector that led to tau hyperphosphorylation, nitration, and accumulation as seen in Alzheimer's disease brain, and the underlying mechanisms, we bilaterally injected SIN-1, a recognized peroxynitrite donor, into the hippocampus of rat brain. We observed that the level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h after drug administration, and these alterations were prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. Concomitantly, we detected a significant activation in glycogen synthase kinase-3beta (GSK-3beta) and p38 MAPKs, including p38alpha, p38beta, and p38delta, but no obvious change was measured in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, in which the activity of 20S proteasome was significantly arrested in SIN-1-injected rats. Further studies demonstrated that the hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis. These results provide the first in vivo evidence showing that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation. Our findings reveal a common upstream stimulator and a potential therapeutic target for Alzheimer-like neurodegeneration.
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PMID:Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms. 1681 18

The serine anti-protease elafin is expressed by monocytes, alveolar macrophages, neutrophils, and at mucosal surfaces and possesses antimicrobial activity. It is also known to reduce lipopolysaccharide-induced neutrophil influx into murine alveoli as well as to abrogate lipopolysaccharide-induced production of matrix metalloprotease 9, macrophage inhibitory protein 2, and tumor necrosis factor-alpha by as-yet unidentified mechanisms. In this report we have shown that elafin inhibits the lipopolysaccharide-induced production of monocyte chemoattractant protein-1 in monocytes by inhibiting AP-1 and NF-kappaB activation. Elafin prevented lipopolysaccharide-induced phosphorylation of AP-1, c-Jun, and JNK but had no effect on phosphorylation of p38. The lipopolysaccharide-induced degradation of IL-1R-associated kinase 1, IkappaBalpha, and IkappaBbeta was inhibited by elafin but phosphorylation of IkappaBalpha was unaffected. Polyubiquitinated protein including polyubiquitinated IkappaBalpha was shown to accumulate in the presence of elafin. These results suggest that inhibition by elafin of lipopolysaccharide-induced AP-1 and NF-kappaB activation occurs via an effect on the ubiquitin-proteasome pathway.
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PMID:Elafin prevents lipopolysaccharide-induced AP-1 and NF-kappaB activation via an effect on the ubiquitin-proteasome pathway. 1698 Mar 10

Caulibugulones are novel but poorly characterized cytotoxic isoquinoline quinones and iminoquinones identified in extracts from the marine bryozoan Caulibugula intermis. We now report that the caulibugulones are selective in vitro inhibitors of the Cdc25 family of cell cycle-controlling protein phosphatases compared with either human vaccinia H1-related phosphatase (VHR) or tyrosine phosphatase 1B (PTP1B). The in vitro inhibition of Cdc25B by caulibugulone A was irreversible and attenuated by reducing agents or catalase, consistent with direct oxidation of the enzyme by reactive oxygen species. Mechanistically, caulibugulone A directly inhibited cellular Cdc25B activity, generated intracellular reactive oxygen species and arrested cells in both G1 and G2/M phases of the cell cycle. Caulibugulone A also caused the selective degradation of Cdc25A protein by a process that was independent of reactive oxygen species production, proteasome activity, and the Chk1 signaling pathway. Instead, caulibugulone A stimulated the phosphorylation and subsequent activation of p38 stress kinase, leading to Cdc25A degradation. Thus, caulibugulone inhibition of cellular Cdc25A and B phosphatases occurred through at least two different mechanisms, leading to pronounced cell cycle arrest.
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PMID:Independent mechanistic inhibition of cdc25 phosphatases by a natural product caulibugulone. 1701 77

The cause of selective dopaminergic neuronal degeneration in Parkinson disease has still not been resolved, but it has been hypothesized that oxidative stress and the ubiquitin-proteasome system are important in the pathogenesis. In this report, we investigated the effect of proteasome inhibition on oxidative stress-induced cytotoxicity in PC12 cells, an in vitro model of Parkinson disease. Treatment with proteasome inhibitors provided significant protection against toxicity by 6-hydroxydopamine and H(2)O(2) in a concentration-dependent manner. The measurement of intracellular reactive oxygen species using 2',7'-dichlorofluorescein diacetate demonstrated that lactacystin, a proteasome inhibitor, significantly reduced 6-hydroxydopamineand H(2)O(2)-induced reactive oxygen species production. Proteasome inhibitors elevated the amount of glutathione and phosphorylated p38 mitogen-activated protein kinase (MAPK) prior to glutathione elevation. The treatment with lactacystin induced the nuclear translocation of NF-E2-related factor 2 (Nrf2) and increased the level of mRNA for gamma-glutamylcysteine synthetase, a rate-limiting enzyme in glutathione synthesis. Furthermore, SB203580, an inhibitor of p38 MAPK, abolished glutathione elevation and cytoprotection by lactacystin. These data suggest that proteasome inhibition afforded cytoprotection against oxidative stress by the elevation of glutathione content, and its elevation was mediated by p38 MAPK phosphorylation.
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PMID:Proteasome inhibition induces glutathione synthesis and protects cells from oxidative stress: relevance to Parkinson disease. 1715 54


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