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)

McKusick-Kaufman syndrome (MKKS) is a recessively inherited human genetic disease characterized by several developmental anomalies. Mutations in the MKKS gene also cause Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder with pleiotropic symptoms. However, little is known about how MKKS mutations lead to disease. Here, we show that disease-causing mutants of MKKS are rapidly degraded via the ubiquitin-proteasome pathway in a manner dependent on HSC70 interacting protein (CHIP), a chaperone-dependent ubiquitin ligase. Although wild-type MKKS quickly shuttles between the centrosome and cytosol in living cells, the rapidly degraded mutants often fail to localize to the centrosome. Inhibition of proteasome functions causes MKKS mutants to form insoluble structures at the centrosome. CHIP and partner chaperones, including heat-shock protein (HSP)70/heat-shock cognate 70 and HSP90, strongly recognize MKKS mutants. Modest knockdown of CHIP by RNA interference moderately inhibited the degradation of MKKS mutants. These results indicate that the MKKS mutants have an abnormal conformation and that chaperone-dependent degradation mediated by CHIP is a key feature of MKKS/BBS diseases.
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PMID:MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination. 1809 50

RNF43 is a recently discovered RING finger protein that is implicated in colon cancer pathogenesis. This protein possesses growth-promoting activity but its mechanism remains unknown. In this study, to gain insight into the biological action of RNF43 we characterized it biochemically and intracellularly. A combination of indirect immunofluorescence analysis and biochemical fractionation experiments suggests that RNF43 resides in the endoplasmic reticulum (ER) as well as in the nuclear envelope. Sucrose density gradient fractionation demonstrates that RNF43 co-exists with emerin, a representative inner nuclear membrane protein in the nuclear subcompartment. The cell-free system with pure components reveals that recombinant RNF43 fused with maltose-binding protein has autoubiquitylation activity. By the yeast two-hybrid screening we identified HAP95, a chromatin-associated protein interfacing the nuclear envelope, as an RNF43-interacting protein and substantiated this interaction in intact cells by the co-immunoprecipitation experiments. HAP95 is ubiquitylated and subjected to a proteasome-dependent degradation pathway, however, the experiments in which 293 cells expressing both RNF43 and HAP95 were treated with a proteasome inhibitor, MG132, show that HAP95 is unlikely to serve as a substrate of RNF43 ubiquitin ligase. These results infer that RNF43 is a resident protein of the ER and, at least partially, the nuclear membrane, with ubiquitin ligase activity and may be involved in cell growth control potentially through the interaction with HAP95.
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PMID:A cancer-associated RING finger protein, RNF43, is a ubiquitin ligase that interacts with a nuclear protein, HAP95. 1831 49

Estrogen receptor alpha (ERalpha) plays an important role in the development and progression of breast cancer, and recent studies showed that ERalpha expression is associated with resistance to hormonal therapy. Therefore, a number of studies have explored ways to deplete ERalpha from breast cancer cells as a new therapy especially for hormone-refractory breast cancer. We reported here that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, effectively depletes ERalpha in breast cancer MCF-7 cells. However, the intrinsic mechanisms by which SAHA decreases ERalpha levels are not clear. Our present data demonstrated that both inhibition of ERalpha mRNA level and promotion of ERalpha degradation by the proteasome contribute to SAHA-induced ERalpha depletion, indicating that SAHA may exert its effects through transcriptional and posttranslational mechanisms. Furthermore, the decrease of ERalpha protein level in MCF-7 cells after SAHA treatment is mainly the result of its rapid degradation by the ubiquitin-proteasome pathway rather than transcriptional inhibition. In addition, we showed that inactivation of the heat shock protein-90 (Hsp90) is involved in SAHA-induced ERalpha degradation, and ubiquitin ligase CHIP (C-terminal Hsc70 interacting protein) enhances SAHA-induced ERalpha degradation. SAHA-induced ERalpha depletion is paralleled with reduction of transcriptional activity of ERalpha and SAHA is able to effectively inhibit cell proliferation and induce apoptosis of MCF-7 cells. Taken together, our results revealed a mechanism for SAHA-induced ERalpha degradation and indicated that SAHA is a suitable pharmacological agent for depletion of ERalpha and a potential choice for breast cancer expressing high ERalpha.
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PMID:Histone deacetylase inhibitor SAHA induces ERalpha degradation in breast cancer MCF-7 cells by CHIP-mediated ubiquitin pathway and inhibits survival signaling. 1834 36

Mutations found in PTEN-induced putative kinase 1 (PINK1), a putative mitochondrial serine/threonine kinase of unknown function, have been linked to autosomal recessive Parkinson's disease. It is suggested that mutations can cause a loss of PINK1 kinase activity and eventually lead to mitochondrial dysfunction. In this report, we examined the subcellular localization of PINK1 and the dynamic kinetics of PINK1 processing and degradation. We also identified cytosolic chaperone heat-shock protein 90 (Hsp90) as an interacting protein of PINK1 by PINK1 co-immunoprecipitation. Immunofluorescence of PINK1 protein and mitochondrial isolation show that the precursor form of PINK1 translocates to the mitochondria and is processed into two cleaved forms of PINK1, which in turn localize more to the cytosolic than mitochondrial fraction. The cleavage does not occur and the uncleaved precursor stays associated with the mitochondria when the mitochondrial membrane potential is disrupted. Metabolic labeling analyses show that the PINK1 processing is rapid and the levels of cleaved forms are tightly regulated. Furthermore, cleaved forms of PINK1 are stabilized by Hsp90 interaction as the loss of Hsp90 activity decreases PINK1 level after mitochondrial processing. Lastly, we also find that cleaved forms of PINK1 are degraded by the proteasome, which is uncommon for mitochondrial proteins. Our findings support a dual subcellular localization, implying that PINK1 can reside in the mitochondria and the cytosol. This raises intriguing functional roles that bridge these two cellular compartments.
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PMID:Characterization of PINK1 processing, stability, and subcellular localization. 1839 67

UbcH6 is a member of an evolutionally conserved subfamily of E2 ubiquitin-conjugating enzymes. In this study, we report that UbcH6 interacts with and ubiquitinates ataxin-1, the spinocerebellar ataxia type 1 gene product. UbcH6 was identified as an ataxin-1-interacting protein using a yeast two-hybrid screen. UbcH6 co-immunoprecipitates and co-localizes with the ataxin-1 protein in the nucleus. Our binding assays showed that ataxin-1 interacts with UbcH6 through its AXH domain. Interestingly, UbcH6 could ubiquitinate ataxin-1 in the absence of an E3 ligase. The expression level of UbcH6 regulated the rate of ataxin-1 degradation. This study demonstrates that UbcH6 and ataxin-1 are E2-substrate cognate pairs in the ubiquitin-proteasome system.
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PMID:UbcH6 interacts with and ubiquitinates the SCA1 gene product ataxin-1. 1843 7

Primate lentiviruses encode four "accessory proteins" including Vif, Vpu, Nef, and Vpr/Vpx. Vif and Vpu counteract the antiviral effects of cellular restrictions to early and late steps in the viral replication cycle. We present evidence that the Vpx proteins of HIV-2/SIV(SM) promote virus infection by antagonizing an antiviral restriction in macrophages. Fusion of macrophages in which Vpx was essential for virus infection, with COS cells in which Vpx was dispensable for virus infection, generated heterokaryons that supported infection by wild-type SIV but not Vpx-deleted SIV. The restriction potently antagonized infection of macrophages by HIV-1, and expression of Vpx in macrophages in trans overcame the restriction to HIV-1 and SIV infection. Vpx was ubiquitylated and both ubiquitylation and the proteasome regulated the activity of Vpx. The ability of Vpx to counteract the restriction to HIV-1 and SIV infection was dependent upon the HIV-1 Vpr interacting protein, damaged DNA binding protein 1 (DDB1), and DDB1 partially substituted for Vpx when fused to Vpr. Our results indicate that macrophage harbor a potent antiviral restriction and that primate lentiviruses have evolved Vpx to counteract this restriction.
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PMID:Primate lentiviral Vpx commandeers DDB1 to counteract a macrophage restriction. 1845 84

The burden of protein misfolding is believed to contribute to aging. However, the links between adaptations to conditions associated with protein misfolding and resistance to the time-dependent attrition of cellular function remain poorly understood. We report that worms lacking aip-1, a homologue of mammalian AIRAP (arsenic-inducible proteasomal 19S regulatory particle-associated protein), are not only impaired in their ability to resist exposure to arsenite but also exhibit shortened lifespan and hypersensitivity to misfolding-prone proteins under normal laboratory conditions. Mammals have a second, constitutively expressed AIRAP-like gene (AIRAPL) that also encodes a proteasome-interacting protein, which shares with AIRAP the property of enhancing peptide accessibility to the proteasome's active site. Genetic rescue experiments suggest that features common to the constitutively expressed worm AIP-1 and mammalian AIRAPL (but missing in the smaller, arsenite-inducible AIRAP) are important to lifespan extension. In worms, a single AIRAP-related protein links proteasomal adaptation to environmental stress with resistance to both proteotoxic insults and maintenance of animal life span under normal conditions.
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PMID:Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans. 1846 95

Rapsyn, an acetylcholine receptor (AChR)-interacting protein, is essential for synapse formation at the neuromuscular junction (NMJ). Like many synaptic proteins, rapsyn turns over rapidly at synapses. However, little is known about molecular mechanisms that govern rapsyn stability. Using a differential mass-spectrometry approach, we identified heat-shock protein 90beta (HSP90beta) as a component in surface AChR clusters. The HSP90beta-AChR interaction required rapsyn and was stimulated by agrin. Inhibition of HSP90beta activity or expression, or disruption of its interaction with rapsyn attenuated agrin-induced formation of AChR clusters in vitro and impaired the development and maintenance of the NMJ in vivo. Finally, we showed that HSP90beta was necessary for rapsyn stabilization and regulated its proteasome-dependent degradation. Together, these results indicate a role of HSP90beta in NMJ development by regulating rapsyn turnover and subsequent AChR cluster formation and maintenance.
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PMID:HSP90 beta regulates rapsyn turnover and subsequent AChR cluster formation and maintenance. 1894 May 91

The telomeric protein TRF1 negatively regulates telomere length by inhibiting telomerase access at the telomere termini, suggesting that the protein level of TRF1 at telomeres is tightly regulated. Regulation of TRF1 protein abundance is essential for proper telomere function and occurs primarily through post-translational modifications of TRF1. Here we describe RLIM, a RING H2 zinc finger protein with intrinsic ubiquitin ligase activity, as a TRF1-interacting protein. RLIM increases TRF1 turnover by targeting it for degradation by the proteasome in a ubiquitin-dependent manner, independently of Fbx4, which is known to interact with and negatively regulate TRF1. Whereas overexpression of RLIM decreases the level of TRF1 protein, depletion of endogenous RLIM expression by small hairpin RNA increases the level of TRF1 and leads to telomere shortening, thereby impairing cell growth. These results demonstrate that RLIM is involved in the negative regulation of TRF1 function through physical interaction and ubiquitin-mediated proteolysis. Hence, RLIM represents a new pathway for telomere maintenance by modulating the level of TRF1 at telomeres.
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PMID:Ubiquitin Ligase RLIM Modulates Telomere Length Homeostasis through a Proteolysis of TRF1. 1916 95

Plant responses against pathogens cause up- and downward shifts in gene expression. To identify differentially expressed genes in a plant-virus interaction, susceptible tomato plants were inoculated with the potyvirus Pepper yellow mosaic virus (PepYMV) and a subtractive library was constructed from inoculated leaves at 72 h after inoculation. Several genes were identified as upregulated, including genes involved in plant defense responses (e.g., pathogenesis-related protein 5), regulation of the cell cycle (e.g., cytokinin-repressed proteins), signal transduction (e.g., CAX-interacting protein 4, SNF1 kinase), transcriptional regulators (e.g., WRKY and SCARECROW transcription factors), stress response proteins (e.g., Hsp90, DNA-J, 20S proteasome alpha subunit B, translationally controlled tumor protein), ubiquitins (e.g., polyubiquitin, ubiquitin activating enzyme 2), among others. Downregulated genes were also identified, which likewise display identity with genes involved in several metabolic pathways. Differential expression of selected genes was validated by macroarray analysis and quantitative real-time polymerase chain reaction. The possible roles played by some of these genes in the viral infection cycle are discussed.
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PMID:Genome-wide analysis of differentially expressed genes during the early stages of tomato infection by a potyvirus. 1924 29


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