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)

We have previously shown that the degradation of c-myc and N-myc in vitro is mediated by the ubiquitin system. However, the role of the system in targeting the myc proteins in vivo and the identity of the conjugating enzymes and possible ancillary proteins involved has remained obscure. Here we report that the degradation of the myc proteins in cells is inhibited by lactacystin and MG132, two inhibitors of the 20S proteasome. Inhibition is accompanied by accumulation of myc-ubiquitin conjugates. Dissection of the ancillary proteins involved revealed that the high-risk human papillomavirus oncoprotein E6-16 stimulates conjugation and subsequent degradation of the myc proteins in vitro. Expression of E6-16 in cells results in significant shortening of the t1/2 of the myc proteins with subsequent decrease in their cellular level. Analysis of the conjugating enzymes revealed that under basal conditions the proteins can be conjugated by two pairs of E2s and E3s-E2-14 kDa and E3alpha involved in the "N-end rule" pathway, and E2-F1 (UbcH7) and E3-Fos involved also in conjugation of c-Fos. In the presence of E6-16, a third pair, E2-F1 and E6-AP mediate conjugation of myc by means of a mechanism that appears to be similar to that involved in the targeting of p53, formation of a myc. E6.E6-AP targeting complex. It is possible that in certain cells E6-mediated targeting of myc prevents myc-induced apoptosis and thus ensures maintenance of viral infection.
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PMID:Basal and human papillomavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway. 965 39

Ubiquitinylation of proteins appears to be mediated by the specific interplay between ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s). However, cognate E3s and/or substrate proteins have been identified for only a few E2s. To identify proteins that can interact with the human E2 UbcH7, a yeast two-hybrid screen was performed. Two proteins were identified and termed human homologue of Drosophila ariadne (HHARI) and UbcH7-associated protein (H7-AP1). Both proteins, which are widely expressed, are characterized by the presence of RING finger and in between RING fingers (IBR) domains. No other overt structural similarity was observed between the two proteins. In vitro binding studies revealed that an N-terminal RING finger motif (HHARI) and the IBR domain (HHARI and H7-AP1) are involved in the interaction of these proteins with UbcH7. Furthermore, binding of these two proteins to UbcH7 is specific insofar that both HHARI and H7-AP1 can bind to the closely related E2, UbcH8, but not to the unrelated E2s UbcH5 and UbcH1. Although it is not clear at present whether HHARI and H7-AP1 serve, for instance, as substrates for UbcH7 or represent proteins with E3 activity, our data suggests that a subset of RING finger/IBR proteins are functionally linked to the ubiquitin/proteasome pathway.
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PMID:The ubiquitin-conjugating enzymes UbcH7 and UbcH8 interact with RING finger/IBR motif-containing domains of HHARI and H7-AP1. 1052 92

The U-box domain has been suggested to be a modified RING finger motif where the metal-coordinating cysteines and histidines have been replaced with other amino acids. Known U-box-containing proteins have been implicated in the ubiquitin/proteasome system. In a search for proteins interacting with the ubiquitin-conjugating enzyme UbcM4/UbcH7, we have identified a novel U-box containing protein, termed UIP5, that is exclusively found in the nucleus as part of a nuclear dot-like structure. Interaction between UbcM4 and UIP5 was observed in vivo and in vitro with bacterially expressed proteins. In addition to UbcM4, several other ubiquitin-conjugating enzymes (E2s) that share the same sequence within the L1 loop bind to UIP5. Mutational analysis showed that the U-box, like the RING finger in other proteins, forms the physical basis for the interaction with E2 enzymes. Further support for the structural similarity between U-box and RING finger comes from the observation that, in both cases, the same regions within the UbcM4 molecule are required for interaction. Our results establish at the molecular level a link between the U-box and the ubiquitin conjugating system and strongly suggest that proteins containing U-box domains are functionally closely related to RING finger proteins.
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PMID:Interaction of the ring finger-related U-box motif of a nuclear dot protein with ubiquitin-conjugating enzymes. 1127 49

Parkin is a product of the Park2 gene the mutation of which causes autosomal recessive juvenile parkinsonism (AR-JP) characterized by selective dopaminergic neuronal death and absence of Lewy bodies. Recently we found that parkin is directly linked to the ubiquitin (Ub)-proteasome pathway as a Ub-protein ligase (E3) collaborating with a Ub-conjugating enzyme (E2) UbcH7. Here we analysed by in situ hybridization the expression of mRNAs for parkin and UbcR7 (rat orthologue of human UbcH7) in the developing rat brain. Parkin mRNA increased in parallel with neuronal maturation, but was unevenly distributed in various brain regions after four postnatal days. The expression pattern of the UbcR7 mRNA was almost identical to that of the parkin mRNA in all cases examined. Both parkin and UbcR7 mRNAs were distributed in neurones but not glial cells. Our findings indicate that parkin is expressed not only in the substantia nigra, but also uniformly in various brain regions in a development-dependent manner. Co-expression of UbcR7 with parkin suggests that UbcR7 may interact with parkin in vivo for ubiquitination of yet unidentified target protein(s).
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PMID:Developmental changes in the expression of parkin and UbcR7, a parkin-interacting and ubiquitin-conjugating enzyme, in rat brain. 1141 39

Autosomal recessive juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson's disease. AR-JP is characterized by selective and massive loss of dopaminergic neurons in the substantia nigra of the midbrain and absence of Lewy bodies, the pathological hallmark of idiopathic Parkinson's disease. Parkin, the causative gene of AR-JP, encodes a 52-kDa protein that is a RING-type ubiquitin (Ub) protein ligase (E3) collaborating with a Ub-conjugating enzyme (E2) belonging to a cognate class of UbcH7 or UbcH8. Analysis of parkin mutations in AP-JP patients reveals that the functional loss of parkin as an E3 enzyme is the molecular basis of AR-JP. Thus it is now clear that AR-JP is due to failure of proteolysis mediated by the Ub-proteasome system and accumulation of as yet unidentified protein(s) causes nigral neuronal death without formation of Lewy bodies. These findings should shed new light on the mechanisms underlying neurodegeneration in sporadic Parkinson's disease as well as AR-JP.
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PMID:Parkin is linked to the ubiquitin pathway. 1169 61

G proteins (Galphabetagamma) are essential signaling molecules, which dissociate into Galpha and Gbetagamma upon activation by heptahelical membrane receptors. We have identified the betagamma subunit complex of the photoreceptor-specific G protein, transducin (T), as a target of the ubiquitin-proteasome pathway. Ubiquitylated species of the transducin gamma-subunit (Tgamma) but not the alpha- or beta-subunits were assembled de novo in bovine photoreceptor preparations. In addition, Tgamma was exclusively ubiquitylated when Tbetagamma was dissociated from Talpha. Ubiquitylation of Tbetagamma on Tgamma was selectively catalyzed by human ubiquitin-conjugating enzymes UbcH5 and UbcH7 and was coincident with degradation of the entire Tbetagamma subunit complex in vitro by a mechanism requiring ATP and the proteasome. We also show that Tbetagamma association with phosducin, a photoreceptor-specific protein of unknown physiological function, blocks Tbetagamma ubiquitylation and subsequent degradation. Phosphorylation of phosducin by Ca(2+)/calmodulin-dependent protein kinase II, which inhibits phosducin-Tbetagamma complex formation, completely restored Tbetagamma ubiquitylation and degradation. We conclude that Tbetagamma is a substrate of the ubiquitin-proteasome pathway and suggest that phosducin serves to protect Tbetagamma following the light-dependent dissociation of Talphabetagamma.
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PMID:Ubiquitylation of the transducin betagamma subunit complex. Regulation by phosducin. 1221 39

A431 resistant variants to epoxomicin (EXM) were established, showing 4.0-6.7 times more resistance to EXM than parental A431P. Both variants demonstrated increased expression of the beta-subunit molecules of 26S proteasome with approximately 2.5 times increased activity. In variant cells, cyclin B and P34cdc2 were over-expressed, whereas P21WAF1 was expressed at a similar level to A431P. Because of the proteasome inhibitor acting as a G2/M blocker, results are to the advantage of resistant cells proliferating in the presence of an inhibitor under a severe environment. Variant cells showed increased expression of epidermal growth factor receptor (EGFR) and decreased expression of mRNA, but also slight accumulation of protein of c-Cbl, which is a negative regulator of EGFR possessing ubiquitin ligase activity to desensitize EGF signaling. UbcH7, acting intimately with c-Cbl, was decreased in level compared to A431P. These phenomena can be regarded as one of the causes of prevention of c-Cbl-mediated down-regulation of EGFR in variant cells, enabling them to live. The anti-apoptotic Bcl-2 mainly consisted of a phosphorylated form with resistance to proteasomal degradation, suggesting that Bcl-2 phosphorylation occurred independently of its apoptotic function. Variant cells showed resistance not only to EXM, but to the 5 proteasome inhibitors, while demonstrating collateral sensitivity to doxorubicin.
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PMID:Establishment and some characteristics of epoxomicin (a proteasome inhibitor) resistant variants of the human squamous cell carcinoma cell line, A431. 1471 20

Recurrent infections with high-risk human papillomaviruses (HPVs) are associated with human cervical cancers. All HPV-associated cancer tissues express the viral oncoproteins E6 and E7, which stimulate cell growth. The expression of E7 is crucial for both the initiation and the maintenance of HPV-associated cancer. Recent studies showed that the level of E7 in cancer cells is regulated by ubiquitin-dependent proteolysis through the 26S proteasome. In this study, we characterized the enzymes involved in the ubiquitin-dependent proteolysis of E7. We show that UbcH7, an E2 ubiquitin-conjugating enzyme, is specifically involved in the ubiquitination of E7. Furthermore, we show that E7 interacts with the SCF (Skp-Cullin-F box) ubiquitin ligase complex containing Cullin 1 (Cul1) and Skp2 and can be ubiquitinated by the Cul1-containing ubiquitin ligase in vitro. Coimmunoprecipitation analyses revealed that E7 interacts with Skp2 and Cul1 in vivo. Finally, the half-life of E7 was found to be significantly longer in Skp2(-/-) mouse embryo fibroblasts (MEFs) than in wild-type MEFs. Taken together, these results suggest that the Cul1- and Skp2-containing ubiquitin ligase plays a role in the ubiquitination and proteolysis of E7. In HPV type 16-containing cervical carcinoma cell line Caski, E7 localizes to both the cytoplasm and the nucleus. Brief treatment of Caski cells with MG132 (a proteasome inhibitor) causes the accumulation of E7 in discrete nuclear bodies. These nuclear bodies are detergent insoluble and contain polyubiquitinated E7. We suggest that E7 relocates to specific nuclear bodies for proteolysis in HPV-containing epithelial cells.
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PMID:The papillomavirus E7 oncoprotein is ubiquitinated by UbcH7 and Cullin 1- and Skp2-containing E3 ligase. 1511 13

The human topoisomerase I- and p53-binding protein topors contains a highly conserved, N-terminal C3HC4-type RING domain that is homologous to the RING domains of known E3 ubiquitin ligases. We demonstrate that topors functions in vitro as a RING-dependent E3 ubiquitin ligase with the E2 enzymes UbcH5a, UbcH5c, and UbcH6 but not with UbcH7, CDC34, or UbcH2b. Additional studies indicate that a conserved tryptophan within the topors RING domain is required for ubiquitination activity. Furthermore, both in vitro and cellular studies implicate p53 as a ubiquitination substrate for topors. Similar to MDM2, overexpression of topors results in a proteasome-dependent decrease in p53 protein expression in a human osteosarcoma cell line. These results are similar to the recent finding that a Drosophila topors orthologue ubiquitinates the Hairy transcriptional repressor and suggest that topors functions as a ubiquitin ligase for multiple transcription factors.
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PMID:Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. 1524 80

There is growing evidence that ubiquitin-proteasome system plays an important role for the generation of circadian rhythms in mice as in Drosophila. Here we examined the expression of ubiquitin-related enzymes (Ubce5, UbcM4, Ube2v, Ube2d2, UchL1, UchL3, Ubp41, UfdlL, beta-TrCP) in the suprachiasmatic nucleus (SCN). At mRNA level, the-expression of these enzymes were faint to moderate except ubiquitin carboxy-terminal hydrolase L1 (UchL1), a dominant deubiquitinating salvaging enzyme. Although strongly expressed in the SCN, UchL1 mRNA did not show the rhythm in the SCN in both light-dark and constant dark conditions.
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PMID:Expression of ubiquitin-related enzymes in the suprachiasmatic nucleus with special reference to ubiquitin carboxy-terminal hydrolase UchL1. 1588 17


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