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 regulates cell functions by modifying various proteins, and cytokeratin (CK) is one of the targets of ubiquitilation. Accumulation of modified CK in various cancers has been demonstrated, and the modified CK increases the aggressiveness of the cancer by disrupting the cytoplasmic CK network and allows them to move freely. The phenotype of the cancer cells may be altered in such a way as to facilitate invasion and metastasis. Modified CK also deregulates mechanisms of mitosis and apoptosis, and leads to immortalization. Therapeutic targeting of ubiquitin or ubiquitilated proteins may reduce the malignant potential of cancer cells.
Semin Cancer Biol 2005 Aug
PMID:Accumulation of ubiquitin-conjugated cytokeratin fragments in tumor cells. 1590 83

Biomarkers that predict response to therapy with inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase remain largely uncharacterized. In order to define proteins involved in potential resistance mechanisms, we examined the effect of gefitinib (ZD1839, Iressa) in the EGFR-positive colon cancer cell lines Caco-2, DiFi, HRT-18 and HT-29. None of them exhibited an activating mutation in exons 19 or 21 of EGFR. Proteome profiling with two-dimensional polyacrylamide gel electrophoresis followed by mass spectrometry revealed 12 proteins differentially expressed in responsive and non-responsive cells. These proteins are involved in metabolic pathways, partially relevant in malignant growth and four of them are known to interact with the EGFR signalling pathway. Ubiquitin carboxyl-terminated hydrolase isozyme L1 (UCH-L1) and galectin-3 are overexpressed in the responsive cell line Caco-2, whereas fatty acid-binding protein (E-FABP) and heat shock protein (hsp) 27 are expressed more in the resistant cell lines HRT-18 and HT-29 suggesting a role in non-responsiveness of cells to gefitinib.
Eur J Cancer 2005 Oct
PMID:Gefitinib-responsive EGFR-positive colorectal cancers have different proteome profiles from non-responsive cell lines. 1611 57

Ubiquitin-dependent proteolysis mediates selective destruction of various cell cycle regulators, transcription factors and tumor suppressors. Gankyrin, a seven ankyrin-repeat protein, was originally identified as an oncoprotein commonly overexpressed in hepatocellular carcinomas and independently as a protein associated with the 19S regulatory complex of the 26S proteasome. Gankyrin also binds to CDK4 and the tumor suppressor RB, and accelerates phosphorylation and proteasomal degradation of RB. Recently, we have shown that gankyrin has an anti-apoptotic activity in cells exposed to DNA-damaging agents. Gankyrin binds to MDM2, a major E3 ubiquitin ligase for p53, and increases ubiquitylation and degradation of p53. Gankyrin increases activities of CDK4 and MDM2, and facilitates targeting of polyubiquitylated proteins to the 26S proteasome. Furthermore, inhibition of gankyrin induces apoptosis in cancer cells. Therefore, gankyrin is a promising target for potential anticancer therapeutic agents.
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PMID:The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation. 1617 71

We recently cloned the full-length cDNA of a tumour-associated protein. The recombinant protein expressed in bacteria and referred to as angiocidin has potent antitumour activity in vivo and in vitro. Angiocidin inhibits tumour growth and angiogenesis by inducing apoptosis in endothelial cells. Based on the sequence similarity of angiocidin to S5a, one of the major polyubiquitin recognition proteins in eukaryotic cells, we postulated that the antiendothelial activity of angiocidin could be due in part to its polyubiquitin binding activity. In support of this hypothesis, we show that angiocidin binds polyubiquitin in vivo with high affinity and colocalises with ubiquitinated proteins on the surface of endothelial cells. Binding is blocked with an antiubiquitin antibody. Angiocidin treatment of endothelial cells transfected with a proteasome fluorescent reporter protein showed a dose-dependent inhibition of proteasome activity and accumulation of polyubiquitinated proteins. Full-length angiocidin bound polyubiquitin while three angiocidin recombinant proteins whose putative polyubiquitin binding sites were mutated either failed to bind polyubiquitin or had significantly diminished binding activity. The in vitro apoptotic activity of these mutants correlated with their polyubiquitin binding activity. These data strongly argue that the apoptotic activity of angiocidin is dependent on its polyubiquitin binding activity.
Br J Cancer 2005 Sep 19
PMID:Endothelial apoptotic activity of angiocidin is dependent on its polyubiquitin binding activity. 1622 12

Recent work indicates that the LKB1 tumour suppressor protein kinase, which is mutated in Peutz-Jeghers cancer syndrome, phosphorylates and activates a group of protein kinases that are related to AMPK (AMP-activated protein kinase). Ten of the 14 AMPK-related protein kinases activated by LKB1, including SIK (salt-induced kinase), MARK (microtubule-affinity-regulating kinase) and BRSK (brain-specific kinase) isoforms, possess a ubiquitin-associated (UBA) domain immediately C-terminal to the kinase catalytic domain. These are the only protein kinases in the human genome known to possess a UBA domain, but their roles in regulating AMPK-related kinases are unknown. We have investigated the roles that the UBA domain may play in regulating these enzymes. Limited proteolysis of MARK2 revealed that the kinase and UBA domains were contained within a fragment that was resistant to trypsin proteolysis. SAXS (small-angle X-ray scattering) analysis of inactive and active LKB1-phosphorylated MARK2 revealed that activation of MARK2 is accompanied by a significant conformational change that alters the orientation of the UBA domain with respect to the catalytic domain. Our results indicate that none of the UBA domains found in AMPK-related kinases interact with polyubiquitin or other ubiquitin-like molecules. Instead, the UBA domains appear to play an essential conformational role and are required for the LKB1-mediated phosphorylation and activation of AMPK-related kinases. This is based on the findings that mutation or removal of the UBA domains of several AMPK-related kinases, including isoforms of MARK, SIK and BRSK, markedly impaired the catalytic activity and LKB1-mediated phosphorylation of these enzymes. We also provide evidence that the UBA domains do not function as LKB1-STRAD (STE20-related adaptor)-MO25 (mouse protein 25) docking/interacting sites and that mutations in the UBA domain of SIK suppressed the ability of SIK to localize within punctate regions of the nucleus. Taken together, these findings suggest that the UBA domains of AMPK-related kinases play an important role in regulating the conformation, activation and localization of these enzymes.
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PMID:The ubiquitin-associated domain of AMPK-related kinases regulates conformation and LKB1-mediated phosphorylation and activation. 1649 40

Ubiquitin-specific protease 14, also known as the 60 kDa subunit of tRNA-guanine transglycosylase (USP14/TGT60 kD), belongs to the ubiquitin-specific processing protease (UBP) family. USP14/TGT60 kD expression in leukemic and colorectal cancer cell lines, and the suppression of such an expression after the induction of cell differentiation have been reported. In the present study, we attempted to clarify whether USP14/TGT60 kD overexpression affects the clinicopathological features of colorectal cancer. Immunohistochemically, USP14/TGT60 kD was absent or weakly localized in the cytoplasm of normal colorectal epithelial cells. In 18 of 99 (18.2%) colorectal cancer patients, USP14/TGT60 kD was strongly detected in the cytoplasm of cancer cells. USP14/TGT60 kD expression correlated with pathological stage (P=0.03), and lymph node (P=0.03) and liver (P=0.03) metastases. Furthermore, the percentage of patients strongly positive for USP14/TGT60 kD expression increased with pathological stage. The overall survival rate was worse in patients with a high USP14/TGT60 kD expression level than in those with a low USP14/TGT60 kD expression level. Our results suggest that USP14/TGT60 kD also controls the fate of proteins that regulate tumor invasion and metastasis.
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PMID:Ubiquitin-specific protease 14 expression in colorectal cancer is associated with liver and lymph node metastases. 1646 9

The ubiquitin-proteasome proteolytic pathway plays a major role in selective protein degradation and regulates various cellular events including cell cycle progression, transcription, DNA repair, signal transduction, and immune response. Ubiquitin, a highly conserved small protein in eukaryotes, attaches to a target protein prior to degradation. The polyubiquitin chain tagged to the target protein is recognized by the 26S proteasome, a high-molecular-mass protease subunit complex, and the protein portion is degraded by the 26S proteasome. The potential of specific proteasome inhibitors, which act as anti-cancer agents, is now under intensive investigation, and bortezomib (PS-341), a proteasome inhibitor, has been recently approved by FDA for multiple myeloma treatment. Since ubiquitination of proteins requires the sequential action of three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), and polyubiquitination is a prerequisite for proteasome-mediated protein degradation, inhibitors of E1, E2, and E3 are reasonably thought to be drug candidates for treatment of diseases related to ubiquitination. Recently, various compounds inhibiting the ubiquitin-proteasome pathway have been isolated from natural resources. We also succeeded in isolating inhibitors against the proteasome and E1 enzyme from marine natural resources. In this review, we summarize the structures and biological activities of natural products that inhibit the ubiquitin-proteasome proteolytic pathway.
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PMID:Natural products inhibiting the ubiquitin-proteasome proteolytic pathway, a target for drug development. 1661 Oct 64

Proteasome is protein complex with proteolytic activity. Proteasomes are in addition to lysosomes the main proteolytic machinery of the eukaryotic cell. Proteins destined for degradation in proteasomes are marked by ubiquitinylation, which consists in attachment of polyubiquitin to relevant protein. The transport of polyubiquitinylated protein follows to proteasome, where protein is cleaved into small peptides. Besides polyubiquitin attachment to protein, monoubiquitinylation of proteins exists and has an important role in DNA repair, transcription of genes, endocytosis and signal transduction. The function of an important transcription factor NF-kappaB is connected with proteasome. NF-kappaB is activated after the proteolysis of its inhibitor IkappaB in proteasome. Ubiqutinylation and degradation of protein in proteasome and the activation of NF-kappaB play significant roles in taking proteins away and in expression of great numbers of genes important for the regulation of the cell cycle and apoptosis of cells. The inhibition of proteasomes has antiproliferative and antiinflammatory effects and opens new therapeutic approaches to a treatment of cancer and some inflammatory diseases. We divided the review into three parts: I. Ubiquitin-proteasome system and the transcription factor NF-kappaB, II. Sumoylation and neddylation as post-translational modification of proteins similar to ubiquitinylation and their significance and lastly III. Using of the knowledge of ubiquitin-proteasome system in cancer and other diseases therapy.
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PMID:[Ubiquitins, proteasomes, sumoylation and therapeutic application today and in future for cancer and other diseases. I. Ubiquitin-proteasome system and the transcription factor NF-kappaB]. 1675 93

Deubiquitinating proteases reverse protein ubiquitination and rescue their target proteins from destruction by the proteasome. USP2, a cysteine protease and a member of the ubiquitin specific protease family, is overexpressed in prostate cancer and stabilizes fatty acid synthase, which has been associated with the malignancy of some aggressive prostate cancers. Here, we report the structure of the human USP2 catalytic domain in complex with ubiquitin. Ubiquitin uses two major sites for the interaction with the protease. Both sites are required simultaneously, as shown by USP2 inhibition assays with peptides and ubiquitin mutants. In addition, a layer of ordered water molecules mediates key interactions between ubiquitin and USP2. As several of those molecules are found at identical positions in the previously solved USP7/ubiquitin-aldehyde complex structure, we suggest a general mechanism of water-mediated ubiquitin recognition by USPs.
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PMID:Structural basis of ubiquitin recognition by the deubiquitinating protease USP2. 1690 3

Polyubiquitin chains linked through the Lys48 residue of ubiquitin are most commonly associated with targeting proteins for proteosomal degradation. In contrast, polyubiquitin chains linked through the Lys63 residue of ubiquitin are associated with nonproteolytic functions such as signal transduction. The mechanism by which Lys63-linked polyubiquitin chains participate in signaling cascades has yet to be determined, but two recent publications (Wu et al., Nat Cell Bio 2006; 8:398-406 and Ea et al., Mol Cell 2006; 22:245-57) shed light on how this distinctive modification functions in NFkappaB activation by TNFalpha. Upon stimulation with TNFalpha, RIP1 undergoes Lys63-linked polyubiquitination. The polyubiquitin chain on RIP1 is recognized and bound by NEMO, the regulatory subunit of the IKK complex, and this binding is essential for NFkappaB activation by TNFalpha. Thus, Lys63-linked polyubiquitin chains critically connect components of NFkappaB signaling in a highly regulated manner.
Cancer Biol Ther 2006 Oct
PMID:Lys63-linked polyubiquitin chains: linking more than just ubiquitin. 1696 79


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