Dubs

Synthetic biology sets out to implement new functions in cells, and to develop a deeper understanding of biological design principles. Elowitz and Leibler [Nature (London) 403, 335 (2000)NATUAS0028-083610.1038/35002125] showed that by rational design of the reaction network, and using existing biological components, they could create a network that exhibits periodic gene expression, dubbed the repressilator. More recently, Stricker et al. [Nature (London) 456, 516 (2008)NATUAS0028-083610.1038/nature07389] presented another synthetic oscillator, called the dual-feedback oscillator, which is more stable...

The molecular mechanism underlying bilirubin neurotoxicity remains obscure. Ubiquitin-proteasome system-mediated proteolysis is pivotal to virtually all cellular processes and cell survival. Here we report for the first time that bilirubin at a clinically relevant elevated level impairs proteasomal function via inhibiting both the 19S proteasome-associated deubiquitinases (USP14 and UCHL5) and the chymotrypsin-like (CT-like) peptidase activity of 20S proteasomes, thereby contributing to bilirubin neurotoxicity...

PURPOSE: Diabetic retinopathy (DR) is the most frequently occurring complication of diabetes. Alterations in ubiquitin-proteasome system (UPS) have been associated with several degenerative disorders. Hence, in this study, we investigated the status and role of UPS and ER stress in the retina of diabetic rats. METHODS: Diabetes was induced in rats by streptozotocin. Retinal markers, ER stress markers, components of UPS, ERAD, and autophagy were analyzed after 2- and 4-months of diabetes...

The levels of hyaluronan, a ubiquitous glycosaminoglycan prominent in the extracellular matrix, is balanced through the actions of hyaluronan-synthesizing enzymes (HAS1, 2 and 3) and degrading hyaluronidases (Hyal 1, 2, 3 and PH20). Hyaluronan accumulates in rapidly remodeling tissues, such as breast cancer, due to deregulated expression of the HAS2 gene and/or alterations of HAS2 activity. The activity of HAS2 is regulated by post-translational modifications, including ubiquitination. In order to identify deubiquitinating enzymes (DUBs) that are involved in de-ubiquitination of HAS2, a complementary (cDNA) library of 69 Flag-HA-tagged human DUBs cloned into retroviral vectors was screened in human embryonic kidney (HEK) 293T cells for their ability to de-ubiquitinate myc-tagged HAS2...

Monoubiquitylation of histone H2B (H2Bub1) is catalyzed mainly by the RNF20/RNF40 complex and erased by multiple deubiquitylating enzymes (DUBs). H2Bub1 influences many aspects of chromatin function, including transcription regulation and DNA repair. Cancer cells often display reduced levels of H2Bub1, and this reduction may contribute to cancer progression. The let-7 family of microRNAs (miRNAs) comprises multiple members with reported tumor-suppressive features, whose expression is frequently downregulated in cancer...

The capacity to allocate visuospatial attention is traditionally considered right-lateralized according to the effects of unilateral cerebral lesions. Contralateral hemi-spatial neglect occurs much more frequently after lesions of the right hemisphere, which has therefore been dubbed as 'dominant'. This pattern of symptoms is supported by functional models that postulate either independence or reciprocal influences between the two hemispheres. Here we specifically explored the dependency of the right hemisphere (RH) from the left hemisphere (LH) in spatial attention...

Amide-proton-transfer weighted (APTw) MRI has emerged as a non-invasive pH-weighted imaging technique for studies of several diseases such as ischemic stroke. However, its pH-sensitivity is relatively low, limiting its capability to detect small pH changes. In this work, computer simulations, protamine phantom experiments, and in vivo gas challenge and experimental stroke in rats showed that, with judicious selection of the saturation pulse power, the amide-CEST at 3.6ppm and guanidyl-CEST signals at 2.0ppm changed in opposite directions with decreased pH...

This paper addresses a novel approach to atomic resolution elemental mapping, demonstrating a method that produces elemental maps with a similar resolution to the established method of electron energy-loss spectroscopy in scanning transmission electron microscopy. Dubbed energy-filtered imaging scanning transmission electron microscopy (EFISTEM) this mode of imaging is, by the quantum mechanical principle of reciprocity, equivalent to tilting the probe in energy-filtered transmission electron microscopy (EFTEM) through a cone and incoherently averaging the results...

Ubiquitin conjugation is a critical signalling process in eukaryotic cells. The precise regulation of deubiquitination is an important component of this signalling cascade. Here we discuss how USP7 (or HAUSP), one of the most abundant deubiquitinating enzymes (DUBs) is regulated by complex formation with regulatory proteins and targets. Full activity of USP7 requires that its C-terminal ubiquitin-like domains fold back onto the catalytic domain, to allow remodelling of the active site to a catalytically competent state by the very C-terminal peptide...

A Lewis cell was designed and constructed for investigating solvent extraction systems by spectrophotometrically monitoring both the organic and aqueous phases in real time. This new Lewis cell was tested and shown to perform well compared to other previously reported Lewis cell designs. The advantage of the new design is that the spectroscopic measurement allows determination of not only metal ion concentrations, but also information regarding chemical speciation - information not available with previous Lewis cell designs...

Post-translational modification of the p53 signaling pathway plays an important role in cell cycle progression and stress-induced apoptosis. Indeed, a large body of work has shown that dysregulation of p53 and its E3 ligase MDM2 by the ubiquitin-proteasome system (UPS) promotes carcinogenesis and malignant transformation. Thus, drug discovery efforts have focused on restoration of wild-type p53 activity or inactivation of oncogenic mutant p53 by targeted inhibition of UPS components, particularly key deubiquitinases (DUBs) of the ubiquitin-specific protease (USP) class...

Excision of multiple fibroadenomas (MF) in separate breast quadrants presents difficulties of number and location of incision(s) and extent of tissue dissection and may be associated with more complications and poorer cosmetic outcome. This is a report of excision of MF in multiple quadrants of the breast using a modification of subcutaneous dissection technique dubbed the circumareolar incision and subdermal tunneling (CAST) dissection. After exposure of the superficial fascia with circumareolar incision, subdermal cone-wise dissection was made to allow mobilization of the segment bearing the lump(s)...

Botulism is characterized by flaccid paralysis, which can be caused by intoxication with any of the seven known serotypes of botulinum neurotoxin (BoNT), all of which disrupt synaptic transmission by endoproteolytic cleavage of SNARE proteins. BoNT serotype A (BoNT/A) has the most prolonged or persistent effects, which can last several months, and exerts its effects by specifically cleaving and inactivating SNAP25. A major factor contributing to the persistence of intoxication is the long half-life of the catalytic light chain, which remains enzymatically active months after entry into cells...

Type-I interferons (IFN-I) are important antiviral drugs which are widely used in clinical therapy of diverse viral infections. However, understanding the detailed mechanisms for IFN-I antiviral signaling remains a major challenge, and may provide novel targets for IFN-based antiviral therapy. So far, the roles of deubiquitinases (DUBs) in regulating IFN-I antiviral activity are still largely unexplored. Here, we find that Ubiquitin C-terminal hydrolase-L3 (UCHL3) plays an important role in regulating type I-interferon (IFN-I) mediated antiviral response...

Proteasome inhibition is an effective therapy for multiple myeloma (MM) patients; however, the emergence of drug resistance is common. Novel therapeutic strategies to overcome proteasome inhibitor resistance are needed. In this study, we examined whether targeting deubiquitylating (DUB) enzymes upstream of 20S proteasome overcomes proteasome inhibitor resistance. Gene expression analysis, immunohistochemical studies of MM patient bone marrow, reverse transcription-PCR and protein analysis show that Rpn11/POH1, a DUB enzyme upstream of 20S proteasome, is more highly expressed in patient MM cells than in normal plasma cells...

OTUB1 (OTU domain-containing, ubiquitin aldehyde binding protein 1) is a deubiquitinating enzyme (DUB) that belongs to the ovarian tumor (OTU) domain protease superfamily. Although it has been demonstrated to play important roles in the development of many kinds of cancer, the mechanism of OTUB1 in hepatocellular carcinoma (HCC) is not clear. The aim of this study was to explore the roles of OTUB1 in HCC progression using cell lines and 115 archived HCC samples. In addition, the clinical outcomes were also analyzed with a special focus on OTUB1 expression in HCC samples...

Recently, a Legionella pneumophila effector protein was shown to have an unprecedented ATP-independent ubiquitin ligase activity that couples phosphoribosylated ubiquitin (PR-Ub) to serine residues of host proteins. A new study published in Cell Research by Qiu et al. reveals that another Legionella effector protein, SidJ, catalyzes deubiquitination of PR-Ub by cleavage of the substrate-linked phosphodiester bond.

Several viruses have been found to encode a deubiquitinating protease (DUB). These viral DUBs are proposed to play a role in regulating innate immune or inflammatory signaling. In human cytomegalovirus (HCMV), the largest tegument protein encoded by UL48 contains DUB activity, but its cellular targets are not known. Here, we show that UL48 and UL45, an HCMV-encoded inactive homolog of cellular ribonucleotide reductase (RNR) large subunit (R1), target receptor-interacting protein kinase 1 (RIP1) to inhibit NF-κB signaling...

BACKGROUND AND AIMS: The main aims of the present study were to formulate an anti-age cream based on vegetal ingredients and ferulic acid and to evaluate the physical characteristics and the efficacy of the cream. METHODS: The active ingredients were Centella asiatica oil, Spilanthes acmella oil, Zingiber officinale extract and ferulic acid. Formulation 1 (F1) was prepared using glyceryl stearate and Ceteareth-25® as emulsifiers and Formulation 2 (F2) using glyceryl stearate and potassium cetyl phosphate, all other ingredients remaining the same...

BACKGROUND: MicroRNAs (miRNAs) play multiple roles in tumor biology. Interestingly, reports from multiple groups suggest that miRNA targets may be coupled through competitive stoichiometric sequestration. Specifically, computational models predicted and experimental assays confirmed that miRNA activity is dependent on miRNA target abundance, and consequently, changes in the abundance of some miRNA targets lead to changes to the regulation and abundance of their other targets. The resulting indirect regulatory influence between miRNA targets resembles competition and has been dubbed competitive endogenous RNA (ceRNA)...