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

Apoptosis signal-regulating kinase 1 (ASK1) is a key regulatory kinase in the proapoptotic response to various stresses. ASK1 phosphorylation of Daxx, an ASK1 activator protein, increases Daxx accumulation in cells and further enhances ASK1 activity through a positive feedback mechanism. Here, we show that ASK1-dependent phosphorylation of Daxx induces Lys(63) (K63)-linked polyubiquitination on Lys(122) of Daxx. Polyubiquitination is dispensable for Daxx accumulation or Daxx interaction with ASK1 because mutant Daxx deficient in polyubiquitin still exhibits ASK1-dependent accumulation and interaction with cellular ASK1. However, K63-linked Daxx polyubiquitination is required for tumor necrosis factor-alpha (TNF-alpha)-induced activation of ASK1. Therefore, K63-linked polyubiquitination of Daxx functions as a molecular switch to initiate and amplify the stress kinase response in the TNF-alpha signaling pathway.
Cancer Res 2009 Oct 01
PMID:Phosphorylation-dependent Lys63-linked polyubiquitination of Daxx is essential for sustained TNF-{alpha}-induced ASK1 activation. 1978 34

Repeated injection of alpha-galactosylceramide, an agonistic ligand for natural killer T (NKT) cells, results in long-term unresponsiveness or anergy, which severely limits its clinical application. However, the molecular mechanisms leading to NKT anergy induction remain unclear. We show here that the decreased IFN-gamma production and failed tumor rejection observed in anergized NKT cells are rescued by Cbl-b deficiency. Cbl-b E3 ligase activity is critical for the anergy induction, as revealed by the similarity between Cbl-b(-/-) and its RING finger mutant NKT cells. Cbl-b binds and promotes monoubiquitination to CARMA1, a critical signaling molecule in NFkappaB activation. Ubiquitin conjugation to CARMA1 disrupts its complex formation with Bcl10 without affecting its protein stability. In addition, CARMA1(-/-) NKT cells are defective in IFN-gamma production. The study identifies an important signaling pathway linking Cbl-b-induced monoubiquitination to NFkappaB activation in NKT cell anergy induction, which may help design approaches for human cancer therapy.
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PMID:Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1. 1981 1

Covalent and reversible post-translational modifications of proteins are a common theme in signaling. Ubiquitin conjugation was originally described to target proteins to proteasomal degradation by ubiquitin polymerization involving lysine (K) 48 residues. Differently linked polymers of polyubiquitin have been found that modify proteins without targeting to proteasomal degradation. Instead this pathway creates docking sites for signaling scaffolds that are key to control the nuclear factor-kappaB (NF-kappaB) pathway. Indeed TRAF-2, TRAF-6, and TRAF-3 are E3 ubiquitin ligases that form K63-linked ubiquitin polymers. Therefore signaling via TNF family receptors, IL1R, IL-18R, T-cell receptor (TCR), and Toll-like receptors (TLR) use this type of post-translational modification. Specific enzymes exist (DUBs) that deactivate this system, degrading K63 polyubiquitin chains. Interestingly, mice deficient in these deubiquitinases develop autoimmunity and inflammation. In carcinogenesis, the K63 polyubiquitin pathway is possibly critical for inflammation-driven tumor promotion. The pathway is also critically involved in costimulation of tumor immunity/immunotherapy as well as in the biology of malignant cells themselves. The elements of this new signaling paradigm offer the opportunity for therapeutic exploitation and drug discovery.
Clin Cancer Res 2009 Nov 15
PMID:Lysine 63 polyubiquitination in immunotherapy and in cancer-promoting inflammation. 1988 90

The ubiquitin proteasome system (UPS) plays a fundamental role in maintaining the correct balance of protein levels inside all living cells. Degradation of proteins by this pathway is essential for most cellular processes including cell signalling, DNA repair, apoptosis and gene transcription. Any disruption to the system is likely to have severe consequences which may lead to disorders including neurodegeneration and cancer. Ubiquitin protein ligases are a group of UPS proteins of particular importance because these proteins determine targeting specificity via recognition of a 'target' protein and its' subsequent 'tagging' with ubiquitin. The 26S proteasome recognises these mutli-ubiquitylated proteins, allowing the correct protein to be degraded at the correct time and place within each cell. Several types of ubiquitin protein ligase have now been identified, however, the largest group by far are those proteins containing a 'RING' motif. In this review, examples will be given whereby abnormal protein ubiquitylation due to absence or inefficiency of a RING protein ligase is proposed to be a key regulator of the disease process. Ways in which we may be able to reverse these effects or manipulate these proteins to restore function will be discussed.
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PMID:Ring finger ubiquitin protein ligases and their implication to the pathogenesis of human diseases. 1992 21

Ubiquitin-specific proteases (USPs) are a subclass of cysteine proteases that catalyze the removal of ubiquitin (either monomeric or chains) from substrates, thus counteracting the activity of E3 ubiquitin ligases. Although the importance of USPs in a multitude of processes, from hereditary cancer to neurodegeneration, is well established, our knowledge on their mode of regulation, substrate specificity and biological function is quite limited. In this study we identify USP47 as a novel interactor of the E3 ubiquitin ligase, Skp1/Cul1/F-box protein beta-transducin repeat-containing protein (SCF(beta-Trcp)). We found that both beta-Trcp1 and beta-Trcp2 bind specifically to USP47, and point mutations in the beta-Trcp WD-repeat region completely abolished USP47 binding, indicating an E3-substrate-type interaction. However, unlike canonical beta-Trcp substrates, USP47 protein levels were neither affected by silencing of beta-Trcp nor modulated in a variety of processes, such as cell-cycle progression, DNA damage checkpoint responses or tumor necrosis factor (TNF) pathway activation. Notably, genetic or siRNA-mediated depletion of USP47 induced accumulation of Cdc25A, decreased cell survival and augmented the cytotoxic effects of anticancer drugs. In conclusion, we showed that USP47, a novel beta-Trcp interactor, regulates cell growth and survival, potentially providing a novel target for anticancer therapies.
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PMID:The ubiquitin-specific protease USP47 is a novel beta-TRCP interactor regulating cell survival. 1996 69

Ubiquitin-positive protein aggregates are a hallmark of many degenerative diseases. Their presence can be induced by dysfunction in protein degradation pathways such as proteasome and autophagy. We now report several lines of evidence suggesting a defect in autophagy in Dictyostelium cells lacking Vmp1 (vacuole membrane protein 1), an endoplasmic reticulum (ER)-resident protein involved in pathological processes such as cancer and pancreatitis. vmp1- null cells are unable to survive starvation or undergo autophagic cell death under the appropriate inductive signals. Moreover, confocal studies using the autophagy marker Atg8 and previous transmission electron microscopy analysis showed defects in autophagosome formation. Although Vmp1 is localized in the ER, we found colocalization with Atg8 suggesting a contribution of both Vmp1 and ER in autophagosome biogenesis or maturation. Interestingly, vmp1- mutant cells showed accumulation of huge ubiquitin-positive protein aggregates containing the autophagy marker GFP-Atg8 and the putative Dictyostelium p62 homologue as described in many degenerative human diseases. The analysis of other Dictyostelium autophagic mutants (atg1-, atg5-, atg6-, atg7- and atg8-) showed a correlation in the severity of their corresponding phenotypes and the presence of ubiquitin-positive protein aggregates suggesting that the deleterious effects associated with development of these aggregates might contribute to the complex phenotypes observed in autophagy deficient mutants. Our results suggest that Vmp1 is required for the clearance of these ubiquitinated protein aggregates through autophagy and highlight a potential role for Vmp1 in protein-aggregation diseases.
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PMID:Autophagy dysfunction and ubiquitin-positive protein aggregates in Dictyostelium cells lacking Vmp1. 2000 61

MCL1 is essential for the survival of stem and progenitor cells of multiple lineages, and is unique among pro-survival BCL2 family members in that it is rapidly turned over through the action of ubiquitin ligases. B- and mantle-cell lymphomas, chronic myeloid leukaemia, and multiple myeloma, however, express abnormally high levels of MCL1, contributing to chemoresistance and disease relapse. The mechanism of MCL1 overexpression in cancer is not well understood. Here we show that the deubiquitinase USP9X stabilizes MCL1 and thereby promotes cell survival. USP9X binds MCL1 and removes the Lys 48-linked polyubiquitin chains that normally mark MCL1 for proteasomal degradation. Increased USP9X expression correlates with increased MCL1 protein in human follicular lymphomas and diffuse large B-cell lymphomas. Moreover, patients with multiple myeloma overexpressing USP9X have a poor prognosis. Knockdown of USP9X increases MCL1 polyubiquitination, which enhances MCL1 turnover and cell killing by the BH3 mimetic ABT-737. These results identify USP9X as a prognostic and therapeutic target, and they show that deubiquitinases may stabilize labile oncoproteins in human malignancies.
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PMID:Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. 2002 29

Protein degradation is the cell's mechanism of eliminating misfolded or unwanted proteins. The pathway by which proteins are degraded occurs through the ubiquitin-proteasome system. Ubiquitin is a small 9-kD (kDa) protein that is attached to proteins. A minimum of four ubiquitins are required for proteins to be recognized by the degradation machinery, known as the 26S proteasome. Defects in ubiquitination have been identified in a number of diseases, including cancer, neurodegenerative diseases, and metabolic disorders. We sought to exploit the delicate balance between protein synthesis and degradation to treat cancer by designing a chimeric molecule, known as Protac (Proteolysis Targeting Chimeric molecule). Protacs are heterobifunctional nanomolecules that are approximately 10 nm in size and can recruit proteins that cause cancer to the ubiquitin-proteasome machinery for degradation. In this review, we discuss the development of this novel technology for the treatment of cancer.
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PMID:Protacs for treatment of cancer. 2007 61

The canonical Wnt signalling pathway is essential for cell fate determination during embryonic development and for the maintenance of adult tissue homeostasis. Deregulation of Wnt signalling leads to developmental defects and is associated with various types of cancer. Here we have used an RNA interference (RNAi) library specifically targeting human deubiquitinating enzymes (DUBs) to screen for new regulators of the canonical Wnt signalling pathway. We found that suppression of the ubiquitin specific protease 4 (USP4) activates beta-catenin dependent transcription. We also show that USP4 is a DUB with dual hydrolysing activity for K(48)- and K(63)-conjugated polyubiquitin chains and interacts with two known Wnt signalling components: the Nemo like kinase (Nlk) and the transcription factor (T-cell factor 4 [TCF4]). Overexpression of a catalytically active Nlk promotes nuclear accumulation of USP4 whereas a subpopulation of TCF4 is a substrate of USP4-dependent deubiquitination. Thus, modulation of USP4 expression may provide a new means to interfere with canonical Wnt signalling in a variety of physiological and pathological conditions.
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PMID:The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway. 2014 12

Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a de-ubiquitinating enzyme expressed in the brain and reproductive tissues as well as certain cancers. The hydrolase activity of UCH-L1 has been implicated in Alzheimer's disease and cancer invasion; therefore, it may represent a therapeutic target for these diseases. The present study was undertaken to identify novel chemical modulators for the hydrolase activity of UCH-L1. To identify chemicals that bind to the active site of UCH-L1, we carried out in silico structure-based drug screening using human UCH-L1 crystal structure data (PDB ID: 2ETL) and virtual compound libraries containing 26,891 and 304,205 compounds. Among the compounds with the highest binding scores, we identified one that potentiates the hydrolase activity of UCH-L1, and six that inhibit the activity in enzymatic assays. These compounds may be useful for research on UCH-L1 function, and could lead to candidate therapeutics for UCH-L1-associated diseases.
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PMID:Identification of a novel chemical potentiator and inhibitors of UCH-L1 by in silico drug screening. 2014 74


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