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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The E6 oncoprotein derived from the tumour-associated human papillomavirus (HPV) types induces the ubiquitin-mediated degradation of several cellular proteins by conjugating them with the cellular ubiquitin ligase E6-AP. This is a HECT domain-containing ligase that was originally identified through its involvement in the E6-mediated degradation of the cellular tumour suppressor protein p53. Here we have investigated, in more detail, the nature of the E6/E6-AP interaction using binding peptides isolated from an E6-specific library. The selected peptides were either predicted or shown to have an alpha-helical core resembling the E6-binding motif on E6-AP, as well as amino acid alterations that increased their affinity for E6. These peptides were potent inhibitors of the E6/E6-AP interaction. Further analysis of the effects of these peptides on the ability of E6 to direct the proteolytic degradation of its various substrates, including p53, Dlg and the MAGI family of proteins, as well as using E6-AP immunodepletion, revealed striking differences in the mechanism by which E6 targets its cellular substrates for degradation. These results suggest that the site on E6 bound by E6-AP is also most likely occupied by other, as yet unidentified, ubiquitin ligases.
J Mol Biol 2004 Jan 23
PMID:Inhibition of E6-induced degradation of its cellular substrates by novel blocking peptides. 1469 92

The expression of human thymidine kinase 1 (hTK1) is highly dependent on the growth states and cell cycle stages in mammalian cells. The amount of hTK1 is significantly increased in the cells during progression to the S and M phases, and becomes barely detectable in the early G(1) phase by a proteolytic control during mitotic exit. This tight regulation is important for providing the correct pool of dTTP for DNA synthesis at the right time in the cell cycle. Here, we investigated the mechanism responsible for mitotic degradation of hTK1. We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. Furthermore, a KEN box sequence located in the C-terminal region of hTK1 is required for its mitotic degradation and interaction capability with Cdh1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif. Taken together, we concluded that activation of the APC/C-Cdh1 complex during mitotic exit controls timing of hTK1 destruction, thus effectively minimizing dTTP formation from the salvage pathway in the early G(1) phase of the cell cycle in mammalian cells.
Mol Cell Biol 2004 Jan
PMID:Mitotic degradation of human thymidine kinase 1 is dependent on the anaphase-promoting complex/cyclosome-CDH1-mediated pathway. 1470 26

Early embryonic lung branching morphogenesis is regulated by many growth factor-mediated pathways. Bone morphogenetic protein 4 (BMP4) is one of the morphogens that stimulate epithelial branching in mouse embryonic lung explant culture. To further understand the molecular mechanisms of BMP4-regulated lung development, we studied the biological role of Smad-ubiquitin regulatory factor 1 (Smurf1), an ubiquitin ligase specific for BMP receptor-regulated Smads, during mouse lung development. The temporo-spatial expression pattern of Smurf1 in mouse embryonic lung was first determined by quantitative real-time PCR and immunohistochemistry. Overexpression of Smurf1 in airway epithelial cells by intratracheal introduction of recombinant adenoviral vector dramatically inhibited embryonic day (E) 11.5 lung explant growth in vitro. This inhibition of lung epithelial branching was restored by coexpression of Smad1 or by addition of soluble BMP4 ligand into the culture medium. Studies at the cellular level show that overexpression of Smurf1 reduced epithelial cell proliferation and differentiation, as documented by reduced PCNA-positive cell index and by reduced mRNA levels for surfactant protein C and Clara cell protein 10 expression. Further studies found that overexpression of Smurf1 reduced BMP-specific Smad1 and Smad5, but not Smad8, protein levels. Thus overexpression of Smurf1 specifically promotes Smad1 and Smad5 ubiquitination and degradation in embryonic lung epithelium, thereby modulating the effects of BMP4 on embryonic lung growth.
Am J Physiol Lung Cell Mol Physiol 2004 Feb
PMID:Overexpression of Smurf1 negatively regulates mouse embryonic lung branching morphogenesis by specifically reducing Smad1 and Smad5 proteins. 1471 1

Von Hippel-Lindau (VHL) syndrome is an autosomal dominant neoplastic disorder characterized by hemangioblastomas of the central nervous system and retina, renal cell carcinomas, pheochromocytoma, and islet cell tumors. This syndrome is closely related with the VHL, a tumor suppressor gene, implying that loss of function or inactivating mutations of both alleles or copies of this gene cause tumor formation. The product of the VHL gene, pVHL, is known to be a component of ubiquitin ligase which targets the transcription factor such as hypoxia-inducible factor (HIF) for degradation in the presence of oxygen. Different VHL mutations confer different site-specific risks of cancer. However, the precise role of pVHL to develop only some specified tumors, especially pheochromocytoma, is not fully understood. We identified a missense mutation of VHL gene, 695 G --> A (R161Q), in a Japanese kindred with type 2A VHL syndrome. We analysed 16 members of this family and detected the same mutation in 8 individuals. All 5 members with tumors possessed the same mutation. Interestingly, one of the identical twins, who had the same R161Q germline mutation, did not show any visible tumors throughout the body, while another of the twins developed a huge pheochromocytoma and retinal angioma. Moreover, one of the affected members in the kindred developed pancreatic neuro-endocrine tumors without pheochromocytoma in spite of possessing the identical germline mutation of the VHL gene. These findings suggest that there are some other additional factors including environmental exposures to initiate and develop tumor formation in the VHL syndrome although abnormalities of VHL gene might be involved.
Int J Mol Med 2004 Mar
PMID:A variety of phenotype with R161Q germline mutation of the von Hippel-Lindau tumor suppressor gene in Japanese kindred. 1476 70

Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.
Hum Mol Genet 2004 Apr 01
PMID:CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. 1496 78

SCF(Fbs1) is a ubiquitin ligase that functions in the endoplasmic reticulum (ER)-associated degradation pathway. Fbs1/Fbx2, a member of the F-box proteins, recognizes high-mannose oligosaccharides. Efficient binding to an N-glycan requires di-N-acetylchitobiose (chitobiose). Here we report the crystal structures of the sugar-binding domain (SBD) of Fbs1 alone and in complex with chitobiose. The SBD is composed of a ten-stranded antiparallel beta-sandwich. The structure of the SBD-chitobiose complex includes hydrogen bonds between Fbs1 and chitobiose and insertion of the methyl group of chitobiose into a small hydrophobic pocket of Fbs1. Moreover, NMR spectroscopy has demonstrated that the amino acid residues adjoining the chitobiose-binding site interact with the outer branches of the carbohydrate moiety. Considering that the innermost chitobiose moieties in N-glycans are usually involved in intramolecular interactions with the polypeptide moieties, we propose that Fbs1 interacts with the chitobiose in unfolded N-glycoprotein, pointing the protein moiety toward E2 for ubiquitination.
Nat Struct Mol Biol 2004 Apr
PMID:Structural basis of sugar-recognizing ubiquitin ligase. 1499 Sep 96

In the February issue of Developmental Cell, Nastasi et al. describe Ozz, a muscle-specific ubiquitin ligase adaptor that regulates myofibril organization. Ozz appears to function in ubiquitination and degradation of membrane-bound, but not cytosolic, beta-catenin, whose turnover may be required for alignment and growth of the sarcomere, the basic contractile unit of myofibers.
Mol Cell 2004 Feb 27
PMID:Ozz; a new name on the long list of beta-catenin's nemeses. 1499 13

Np95 is an important determinant in cell cycle progression. Its expression is tightly regulated and becomes detectable shortly before the entry of cells into S phase. Accordingly, Np95 is absolutely required for the G1/S transition. Its continued expression throughout the S/G2/M phases further suggests additional roles. Indeed, Np95 has been implicated in DNA damage response. Here, we show that Np95 is tightly bound to chromatin in vivo and that it binds to histones in vivo and in vitro. The binding to histones is direct and shows a remarkable preference for histone H3 and its N-terminal tail. A novel protein domain, the SRA-YDG domain, contained in Np95 is indispensable both for the interaction with histones and for chromatin binding in vivo. Np95 contains a RING finger. We show that this domain confers E3 ubiquitin ligase activity on Np95, which is specific for core histones, in vitro. Finally, Np95 shows specific E3 activity for histone H3 when the endogenous core octamer, coimmunoprecipitating with Np95, is used as a substrate. Histone ubiquitination is an important determinant in the regulation of chromatin structure and gene transcription. Thus, the demonstration that Np95 is a chromatin-associated ubiquitin ligase suggests possible molecular mechanisms for its action as a cell cycle regulator.
Mol Cell Biol 2004 Mar
PMID:Np95 is a histone-binding protein endowed with ubiquitin ligase activity. 1499 89

Pma1-7 is a mutant plasma membrane ATPase that is impaired in targeting to the cell surface at 37 degrees C and is delivered instead to the endosomal/vacuolar pathway for degradation. We have proposed that Pma1-7 is a substrate for a Golgibased quality control mechanism. By contrast with wild-type Pma1, Pma1-7 is ubiquitinated. Ubiquitination and endosomal targeting of Pma1-7 is dependent on the Rsp5-Bul1-Bul2 ubiquitin ligase protein complex but not the transmembrane ubiquitin ligase Tul1. Analysis of Pma1-7 ubiquitination in mutants blocked in protein transport at various steps of the secretory pathway suggests that ubiquitination occurs after ER exit but before endosomal entry. In the absence of ubiquitination in rsp5-1 cells, Pma1-7 is delivered to the cell surface and remains stable. Nevertheless, Pma1-7 remains impaired in association with detergent-insoluble glycolipid-enriched complexes in rsp5-1 cells, suggesting that ubiquitination is not the cause of Pma1-7 exclusion from rafts. In vps1 cells in which protein transport into the endosomal pathway is blocked, Pma1-7 is routed to the cell surface. On arrival at the plasma membrane in vps1 cells, Pma1-7 remains stable and its ubiquitination disappears, suggesting deubiquitination activity at the cell surface. We suggest that Pma1-7 sorting and fate are regulated by ubiquitination.
Mol Biol Cell 2004 May
PMID:Ubiquitin-mediated targeting of a mutant plasma membrane ATPase, Pma1-7, to the endosomal/vacuolar system in yeast. 1502 Jul 11

Our previous study showed that ubiquitination of p53 is reversible and that the ubiquitin hydrolase HAUSP can stabilize p53 by deubiquitination. Here, we found that partial reduction of endogenous HAUSP levels by RNAi indeed destabilizes endogenous p53; surprisingly, however, nearly complete ablation of HAUSP stabilizes and activates p53. We further show that this phenomenon occurs because HAUSP stabilizes Mdm2 in a p53-independent manner, providing an interesting feedback loop in p53 regulation. Notably, HAUSP is required for Mdm2 stability in normal cells; in HAUSP-ablated cells, self-ubiquitinated-Mdm2 becomes extremely unstable, leading to indirect p53 activation. Furthermore, this feedback regulation is specific to Mdm2; in HeLa cells, where p53 is preferentially degraded by viral E6-dependent ubiquitination, depletion of HAUSP fails to activate p53. This study provides an example of an ubiquitin ligase (Mdm2) that is directly regulated by a deubiquitinase (HAUSP) and also reveals a dynamic role of HAUSP in the p53-Mdm2 pathway.
Mol Cell 2004 Mar 26
PMID:A dynamic role of HAUSP in the p53-Mdm2 pathway. 1505 80


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