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)

Ubiquitin-mediated proteolysis is involved in the turnover of many short-lived regulatory proteins. This pathway leads to the covalent attachment of one or more multiubiquitin chains to target substrates which are then degraded by the 26S multicatalytic proteasome complex. Multiple classes of regulatory enzymes have been identified that mediate either ubiquitin conjugation or ubiquitin deconjugation from target substrates. Timed destruction of cellular regulators by the ubiquitin-proteasome pathway plays a critical role in ensuring normal cellular processes. This review provides multiple examples of key growth regulatory proteins whose levels are regulated by ubiquitin-mediated proteolysis. Pharmacological intervention which alters the half-lives of these cellular proteins may have wide therapeutic potential. Specifically, prevention of p53 ubiquitination (and subsequent degradation) in human papilloma virus positive tumors, and perhaps all tumors retaining wild-type p53 but lacking the retinoblastoma gene function, should lead to programmed cell death. Specific inhibitors of p27 and cyclin B ubiquitination are predicted to be potent antiproliferative agents. Inhibitors of IkappaB ubiquitination should prevent NFkappaB activation and may have utility in a variety of autoimmune and inflammatory conditions. Finally, we present a case for deubiquitination enzymes as novel, potential drug targets.
J Mol Med (Berl) 1997 Jan
PMID:The ubiquitin-mediated proteolytic pathway as a therapeutic area. 902 Mar 79

The intersegmental muscles (ISMs) of the tobacco hawkmoth, Manduca sexta, undergo programmed cell death (PCD) following adult eclosion in response to a decline in the circulating titer of the hormone 20-hydroxyecdysone. The ability of the ISMs to die requires de novo gene expression and a number of cDNAs representing differentially expressed genes have been isolated from condemned cells. One of the genes that is dramatically up-regulated with ISM death is polyubiquitin, which has been shown in many organisms to function as a heat shock protein and as an essential mediator of proteolysis. Northern blot analysis of ISM RNA samples pooled from multiple individuals demonstrated the presence of several polyubiquitin transcripts. In this study, we sought to determine: 1) if these transcripts were the product of multiple genes or multiple alleles, and 2) if all polyubiquitin genes/alleles in the moth are regulated by both heat shock and the endocrine signals that regulate death. Data from Southern blot analysis suggested that the Manduca genome has a single polyubiquitin gene that is represented by multiple alleles. Transcript analysis supported the hypothesis that all polyubiquitin alleles are regulated by both heat shock and the hormonal cues that regulate muscle death. Polyubiquitin transcripts accumulated to much higher levels and had longer half-lives following hormonal induction relative to that seen in response to heat shock. These data suggest that there are multiple polyubiquitin alleles in the laboratory population of Manduca, all of which share common regulatory sequences that drive expression to meet the needs for proteolysis involved in both heat stress and death.
Insect Biochem Mol Biol 1996 Dec
PMID:Allelic variation of the polyubiquitin gene in the tobacco hawkmoth, Manduca sexta, and its regulation by heat shock and programmed cell death. 903 86

Carbon and nitrogen regulation of UBI4, the stress-inducible polyubiquitin gene of Saccharomyces cerevisiae, was investigated using a UBI4 promoter-LacZ fusion gene (UBI4-LacZ). Expression of this gene in cells grown on different media indicated that the UBI4 promoter is more active during growth on respiratory than on fermentable carbon sources but is not subject to appreciable control by nitrogen catabolite repression. UBI4-LacZ expression was virtually identical in cells having constitutively high (ras2, sra1-13) or constitutively low (ras2) levels of cyclic AMP-dependent protein kinase activity, indicating that this kinase does not exert a major influence on UBI4 expression. Catabolite derepression control of the UBI4 promoter was confirmed by measurements of UBI4-LacZ expression in hap mutant and wild-type strains before and after transfer from glucose to lactate. Mutagenesis of the perfect consensus for HAP2/3/4 complex binding at position -542 resulted in considerable reduction of UBI4 promoter derepression with respiratory adaptation in HAP wild-type cells and abolished the reduced UBI4-LacZ derepression normally seen when aerobic cultures of the hap1 mutant are transferred from glucose to lactate. This HAP2/3/4 binding site is therefore a major element contributing to catabolite derepression of the UBI4 promoter, although data obtained with hapl mutant cells indicated that HAP1 also contributes to this derepression. The HAP2/3/4 and HAP1 systems are normally found to activate genes for mitochondrial (respiratory) functions. Their involvement in mediating higher activity of the UBI4 promoter during respiratory growth may reflect the contribution of UBI4 expression to tolerance of oxidative stress.
Mol Gen Genet 1997 Jan 27
PMID:UBI4, the polyubiquitin gene of Saccharomyces cerevisiae, is a heat shock gene that is also subject to catabolite derepression control. 903 3

Ubiquitin, a heat-shock protein highly expressed during spermatogenesis, plays an essential role in the differentiation of the germinal cells, particularly in the structural changes of chromatin taking place at the end of the process. To shed light on the mechanisms that modulate transcriptional activity of the heat-shock inducible polyubiquitin gene UbI during spermatogenesis and stabilize the message when transcription is not longer active, we have compared the characteristics of UbI transcripts in mature and immature testes and somatic cells. In mature chicken testes, transcription starts at a site placed closer to the heat-shock promoters than in somatic tissues. This site is upstream from the TATA box used in somatic cells. In addition, UbI transcript undergoes an alternative splicing that produces a longer 5' untranslated region in mature testis. These findings may provide a basis for the observed increase in expression of UbI in mature chicken testes and for the stability of the message when transcription ceases at the end of spermatogenesis.
Mol Reprod Dev 1997 Apr
PMID:Heat-shock inducible polyubiquitin gene UbI undergoes alternative initiation and alternative splicing in mature chicken testes. 909 93

The polyubiquitin gene Ubi.U4 is expressed in a complex pattern during cell division and plant development in Nicotiana tabacum. Plants transformed with the uidA reporter gene placed under the control of the proximal 263 bp of the promoter are able to express GUS activity in dividing cells. This expression is modified when a G-box-like motif is mutated. In order to clarify the transcriptional regulation of this gene, we analysed positively regulating sequences in this proximal promoter by electrophoretic mobility-shift assays (EMSA). We observed that the G-box-like element gave rise to only weak protein-DNA bands but that a new motif, GCTGTAC, directs formation of numerous, distinctive, strong and developmentally specific shifts with nuclear extracts prepared from various different developmental stages and from dividing cells. Point mutations within this motif abolish formation of the protein-DNA complexes and reduce promoter activity in transient expression assays. This novel putative cis-acting element, which we called the U-box, present 12 nucleotides upstream of the G-box-like element, thus seems also to be critical for Ubi.U4 promoter activity.
Mol Gen Genet 1997 Apr 16
PMID:Identification of a new cis-regulatory element in a Nicotiana tabacum polyubiquitin gene promoter. 915 Feb 59

We have investigated three aspects of nucleotide usage by the 26S proteasome and its regulatory complex (RC). Both particles hydrolyze the four major ribonucleotides, but ATP and CTP have substantially lower Kms for hydrolysis than do GTP and UTP. The Km for ATP hydrolysis is 15 microm for the 26S proteasome and 30 microm for the regulatory complex. Formation of the 26S proteasome from the RC and the 20S proteasome requires about 5 microm ATP. Although measurable degradation of Ubiquitin(Ub)-lysozyme conjugates occurs in the presence of CTP, GTP, and UTP, the best nucleotide for Ub-conjugate degradation by the 26S proteasome is ATP, with an estimated Km of 12 microm. In summary, our studies show that micromolar concentrations of ATP are sufficient for several 26S proteasome activities.
Mol Biol Rep 1997 Mar
PMID:Effects of nucleotides on assembly of the 26S proteasome and degradation of ubiquitin conjugates. 922 75

Ubiquitin protein conjugates are commonly detected in neuronal brain inclusions of patients with neurodegenerative disorders. The failure to eliminate the ubiquitin-protein deposits in the degenerating neurons may result from changes in the activity of the ubiquitin/ATP-dependent proteolytic pathway. This proteolytic pathway plays a major role in the degradation of short lived, abnormal and denatured proteins. Cadmium is a potent cell poison and is known to affect the ubiquitin pathway and to cause oxidative stress. Increases in protein mixed-disulfides (Pr-SSG) and decreases in glutathione (GSH) are often used as markers of oxidative stress. To investigate the relationship between the ubiquitin pathway and cellular glutathione (GSH), we treated HT4 cells (a mouse neuronal cell line) and rat mesencephalic primary cultures with different concentrations of the heavy metal. We observed marked increases in Pr-SSG as well as decreases in GSH, after exposure of HT4 cells or primary mesencephalic cultures to Cd2+. Furthermore, our results show that Cd2+ induced the accumulation of ubiquitinated proteins. Detection was by Western blotting of total cell extracts probed with antibodies that recognize ubiquitin-protein conjugates. These results suggest that the ubiquitin-pathway is closely involved in the cell response to cadmium-mediated oxidative stress.
Mol Biol Rep 1997 Mar
PMID:Accumulation of ubiquitinated proteins in mouse neuronal cells induced by oxidative stress. 922 78

The ubiquitin-specific proteases (UBPs) are a class of enzymes vital to the ubiquitin pathway. These enzymes cleave ubiquitin at its C-terminus from two types of substrates containing (i) ubiquitin in an alpha-amino linkage, as found in the primary ubiquitin translation products, polyubiquitin and ubiquitin-ribosomal fusion proteins, or (ii) ubiquitin in an epsilon-amino linkage, as found in multiubiquitin chains either unattached or conjugated to cellular proteins. We have isolated cDNAs for two Arabidopsis thaliana genes, AtUBP3 and AtUBP4, which encode UBPs that are 93% identical. These two cDNAs represent the only two members of this subgroup and encode the smallest UBPs described to date in any organism. Using in vivo assays in Escherichia coli that allow the coexpression of a UBP with a putative substrate, we have shown that AtUBP3 and AtUBP4 can specifically deubiquitinate the artificial substrate Ub-X-beta-gal but cannot act upon the natural alpha-amino-linked ubiquitin fusions Arabidopsis Ub-CEP52 and Arabidopsis polyubiquitin. Affinity-purified antibody prepared against AtUBP3 expressed in E. coli recognizes both AtUBP3 and AtUBP4. AtUBP3 and/or AtUBP4 are present in all Arabidopsis organs examined and at multiple developmental stages. Subcellular localization studies show that AtUBP3 and/or AtUBP4 are present in nuclear extracts. Possible physiological roles for these UBPs are discussed.
Mol Gen Genet 1997 Jul
PMID:AtUBP3 and AtUBP4 are two closely related Arabidopsis thaliana ubiquitin-specific proteases present in the nucleus. 926 21

Polyubiquitin genes encode the highly conserved 76-amino acid protein ubiquitin that is covalently attached to substrate proteins targeting most for degradation. Polyubiquitin genes are characterized by the presence of tandem repeats of the 228 bp that encode a ubiquitin monomer. Five polyubiquitin genes UBQ3, UBQ4, UBQ10, UBQ11, and UBQ14, previously isolated from Arabidopsis thaliana ecotype Columbia [10] encode identical mature ubiquitin proteins, but differ in synonymous substitutions, nature of amino acids terminating the open reading frame, and in the number of ubiquitin repeats. The presence of these five genes in nine other Arabidopsis ecotypes was verified by polymerase chain reaction (PCR). Size differences in UBQ3 and UBQ11 amplified products from several ecotypes were observed, suggesting that alleles differ in ubiquitin repeat number. DNA sequence of UBQ11 alleles from each size class (ecotypes Be-0, Ler. and Rld-0) verified that PCR product size differences resulted from changes in the number of ubiquitin repeats. Nucleotide sequence between two UBQ11 alleles containing the same number of repeats was identical. Transcript size differences for UBQ3 and UBQ11 mRNAs between ecotypes Columbia and Landsberg indicated that repeat number changes did not inactivate these genes. Nucleotide sequence comparisons between UBQ11 repeats from different ecotypes suggest that first repeats are related to each other and last repeats are related to each other. We hypothesize that changes in UBQ11 ubiquitin repeat number occurred via the contraction and/or expansion of specific internal repeats or portions thereof by misalignment of alleles and recombination, most likely via unequal crossing-over events.
Plant Mol Biol 1997 Jul
PMID:A model for the evolution of polyubiquitin genes from the study of Arabidopsis thaliana ecotypes. 927 65

Traversal from G1 to S-phase in cycling cells of budding yeast is dependent on the destruction of the S-phase cyclin/CDK inhibitor SIC1. Genetic data suggest that SIC1 proteolysis is mediated by the ubiquitin pathway and requires the action of CDC34, CDC4, CDC53, SKP1, and CLN/CDC28. As a first step in defining the functions of the corresponding gene products, we have reconstituted SIC1 multiubiquitination in DEAE-fractionated yeast extract. Multiubiquitination depends on cyclin/CDC28 protein kinase and the CDC34 ubiquitin-conjugating enzyme. Ubiquitin chain formation is abrogated in cdc4ts mutant extracts and assembly restored by the addition of exogenous CDC4, suggesting a direct role for this protein in SIC1 multiubiquitination. Deletion analysis of SIC1 indicates that the N-terminal 160 residues are both necessary and sufficient to serve as substrate for CDC34-dependent ubiquitination. The complementary C-terminal segment of SIC1 binds to the S-phase cyclin CLB5, indicating a modular structure for SIC1.
Mol Biol Cell 1997 Aug
PMID:SIC1 is ubiquitinated in vitro by a pathway that requires CDC4, CDC34, and cyclin/CDK activities. 928 16


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