Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nucleotide sequence of the polyubiquitin gene UbC of HeLa S3 cells and its upstream region was determined and characterized. Recognition sequences for the transcription factors HSF, NF kappa B, AP-1(c-jun), NF-IL6 and Sp1 were found in the upstream control region, a result consistent with the observation of a distinct regulatory response for the UbC gene compared with that of another polyubiquitin gene UbB. Employing a PCR procedure to amplify the entire coding region from genomic DNA, we found a heterogeneity in the repeat number (eight and nine repeats) of the ubiquitin coding units, which resulted from an apparent deletion of either the seventh or the eighth unit in the predominant nine-ubiquitin-unit coding gene. In addition, by comparison with the nucleotide sequence of the UbC gene of human leukocytes previously determined, we found a significant number of nucleotide discrepancies. However, these discrepancies could be substantially reduced by realigning the units so that the first and second ubiquitin units of the sequence determined here are translocated to the boundary between the eighth and the ninth units.
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PMID:Heterogeneous structure of the polyubiquitin gene UbC of HeLa S3 cells. 891 96

UFD1L (Ubiquitin Fusion Degradation 1 Like) gene encodes for a component of a multi-complex involved in the degradation of ubiquitin fusion proteins. The gene maps on chromosome 22q11, in a region commonly deleted in severe congenital disorders such as DiGeorge (DGS) and velo-cardio-facial (VCFS) syndromes. UFD1L is a single copy gene ubiquitously expressed in high levels in the pharyngeal pouches and fourth branchial arch artery during development. To understand the regulation of UFD1L expression we performed a functional analysis of its 5' regulatory region. 5'-RACE and primer extension analyses revealed the presence of different transcription start sites in adult and fetal tissues. UFD1L 5' flanking region contains a TATA-box motif and is also very GC-rich with a CpG island encompassing exon 1. Transcriptional activity of this region was examined by transfection experiments of promoter-GFP reporter gene constructs in a human epithelial cell line. These experiments revealed the importance of the region between -17 and -463 nt which contains the TATA-box. EMSA assay resulted in the detection of five functional consensus sequences respectively for the transcription complex TFIID and for the transcription factors AP-1 (one site), AP-2 (one) and Sp1 (two).
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PMID:Functional characterization of the 5' flanking region of human ubiquitin fusion degradation 1 like gene (UFD1L). 1197 12

In uremia, muscle wasting involves increased glucocorticoid production and activation of the ubiquitin-proteasome proteolytic pathway, including increased expression of ubiquitin. Previously, we reported that glucocorticoids stimulate ubiquitin transcription by a mechanism involving Sp1 in L6 muscle cells (Marinovic AC, Zheng B, Mitch WE, Price SR. J Biol Chem 277: 16673-16681, 2002). This finding was surprising because Sp1 is a general transcriptional activator. To better understand the mechanism of glucocorticoid-induced ubiquitin (UbC) gene transcription, we examined whether this response occurs in many organs or uniquely in skeletal muscle. Glucocorticoid-responsive cells of different organs were transfected with a human UbC promoter-luciferase reporter plasmid; dexamethasone stimulated UbC reporter activity 220% (P < 0.05) in L6 skeletal muscle cells but not in HepG2 hepatocytes, NRK kidney cells, CaCo-2 colon cells, or H9c2 cardiomyocytes. Transactivation of the Sp1-responsive SV40 viral promoter was also increased in muscle but not in other nonmuscle cells. The muscle-specific nature of the UbC response was confirmed in vivo in rats with insulin deficiency, a condition associated with high glucocorticoid production: UbC mRNA was elevated in skeletal muscle but not in liver, kidney, intestine, or heart. Electrophoretic mobility shift assays and in vivo genomic footprinting demonstrated that insulin deficiency increased Sp1 binding to GC-rich elements in the UbC promoter. Thus glucocorticoids increase UbC transcription by a mechanism involving Sp1 that is unique to muscle.
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PMID:Tissue-specific regulation of ubiquitin (UbC) transcription by glucocorticoids: in vivo and in vitro analyses. 1695 42

Ubiquitin (Ub) plays a crucial role in almost every aspect of cellular functions. It is encoded by four genes, of which UbC is known to meet cell demand for ubiquitin in both basal and stressful conditions. To understand the molecular mechanisms regulating UbC gene expression, we performed a functional characterization of the UbC promoter. Deletion analyses on the 5' end of the -916/+878 promoter region, excluded the functional importance of nt -916/-371 in the transcriptional regulation of the gene, while 3' deletions revealed that intron removal (nt+65/+876) resulted in a marked reduction of promoter activity in all the reporter constructs, regardless of the cell types. Intron substitution with a heterologous chimeric intron failed to restore promoter activity, thus allowing to exclude that the splicing event, per se, can be responsible for the intron-mediated burst of transcription. Gel shift assays demonstrated nuclear factor binding with the +137/+766 intron region. Reporter constructs carrying partial intron deletions confirmed that this sequence is, indeed, required for maximal transcriptional activity. Computer-based analysis found potential Sp1 binding motifs within the intron sequence and electrophoretic mobility shift and supershift assays demonstrated that both Sp1 and Sp3 transcription factors interact, in vitro, with the UbC intron, at multiple binding sites. Moreover, ectopic expression of Sp1 and Sp3 revealed that both transcription factors positively regulate UbC promoter activity. Collectively, our data highlight the very new evidence that the 5'-UTR intron is crucial in regulating UbC gene expression and provide insights into the pivotal role of Sp1/Sp3 binding to the intronic enhancer in the regulation of UbC transcription.
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PMID:A potent enhancer element in the 5'-UTR intron is crucial for transcriptional regulation of the human ubiquitin C gene. 1973 23

Muscle atrophy is a consequence of chronic diseases (e.g., diabetes) and glucocorticoid-induced insulin resistance that results from enhanced activity of the ubiquitin-proteasome pathway. The PI3K/Akt pathway inhibits the FOXO-mediated transcription of the muscle-specific E3 ligase atrogin-1/MAFbx (AT-1), whereas the MEK/ERK pathway increases Sp1 activity and ubiquitin (UbC) expression. The observations raise a question about how the transcription of these atrogenes is synchronized in atrophic muscle. We tested a signaling model in which FOXO3a mediates crosstalk between the PI3K/Akt and MEK/ERK pathways to coordinate AT-1 and UbC expression. In rat L6 myotubes, dexamethasone (> or = 24 h) reduced insulin receptor substrate (IRS)-1 protein and PI3K/Akt signaling and increased AT-1 mRNA. IRS-2 protein, MEK/ERK signaling, Sp1 phosphorylation, and UbC transcription were simultaneously increased. Knockdown of IRS-1 using small interfering RNA or adenovirus-mediated expression of constitutively activated FOXO3a increased IRS-2 protein, MEK/ERK signaling, and UbC expression. Changes in PI3K/Akt and MEK/ERK signaling were recapitulated in rat muscles undergoing atrophy due to streptozotocin-induced insulin deficiency and concurrently elevated glucocorticoid production. IRS-1 and Akt phosphorylation were decreased, whereas MEK/ERK signaling and expression of IRS-2, UbC and AT-1 were increased. We conclude that FOXO3a mediates a reciprocal communication between the IRS-1/PI3K/Akt and IRS-2/MEK/ERK pathways that coordinates AT-1 and ubiquitin expression during muscle atrophy.
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PMID:FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy. 2037 24

Ubiquitin-specific processing enzyme 22 (USP22) plays a direct role in regulating cell cycle, and its overexpression has been reported to be involved in tumor progression. However, little is known about the regulation of USP22 transcription. In this study, we cloned and characterized the human USP22 promoter. Using 5' RACE (rapid amplification of cDNA ends) analysis, the transcriptional initiation site was identified. Promoter deletion analysis showed that the sequence between -210 and -7 contains the basal promoter for USP22 in human fibroblast and tumor cells. Surprisingly, mutations in a putative Sp1 binding site immediately upstream of the USP22 transcriptional start site (-13 to -7) resulted in a significant induction of promoter activity. Further study revealed that Sp1 binds to this site in human normal fibroblast cells, and treatment with the Sp1 inhibitor mithramycin A led to a marked increase in USP22 transcript levels. Forced expression of exogenous Sp1 repressed the USP22 promoter activity in HeLa cells. In contrast, knockdown of Sp1 enhanced USP22 promoter activity and mRNA levels. These data suggest that Sp1 is a crucial regulator of USP22 transcription.
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PMID:Cloning and characterization of the human USP22 gene promoter. 2330 Jul 49

Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain-containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease-modifying strategies in proteinopathies.
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PMID:A protein quality control pathway regulated by linear ubiquitination. 3097 87