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The COP9 Signalosome Controls Adipocyte Differentiation by Regulating CHOP Protein Stability  [PDF]
Xiaohua Huang, Wolfgang Dubiel
Engineering (ENG) , 2012, DOI: 10.4236/eng.2012.410B050

Obesity is a serious health problem of our time. Dysfunction of adipogenesis, the differentiation of adipocytes, is a hallmark of obesity. Therefore here we investigate the role of the COP9 signalosome and of CHOP in the differentiation of LiSa-2 preadipocytes.

Downregulation of COP9 signalosome subunits differentially affects the CSN complex and target protein stability
Andreas Peth, Christoph Berndt, Wolfgang Henke, Wolfgang Dubiel
BMC Biochemistry , 2007, DOI: 10.1186/1471-2091-8-27
Abstract: Permanent knockdowns of CSN1 and CSN3 led to a reduction of the subunits to approximately 40%, which is accompanied by a proportional decrease of the CSN holocomplex. In contrast, downregulation of CSN5 in HeLa cells reduced the CSN5 protein below 20% without significant effects on the remaining complex. The CRL component Rbx1 was characterized by accelerated proteolysis in siCSN1 and siCSN3 and also in siCSN5 cells, however, with lesser extent. Immunoprecipitated CSN complex from siCSN5 cells was less effective in phosphorylating c-Jun and p27. Accelerated degradation of c-Jun in siCSN5 cells was rescued by overexpression of CSN5 as well as of the deneddylation mutant CSN5D151N. Overexpression of CSN5 cannot rescue c-Jun destabilization in siCSN1.There exists a coordinated downregulation of CSN subunits in the CSN1 and CSN3 knockdowns. The underlying regulatory mechanisms are obscure. CSN5 seems to possess a specific status in HeLa cells. Its reduction is not connected with coordinated downregulation of other subunits. CSN knockdowns confirm that the stabilization of the CRL component Rbx1 is a major CSN function. In addition, downregulation of CSN subunits influences the stability of important cellular regulators such as c-Jun and p27.The COP9 signalosome (CSN) is a conserved protein complex, which controls eukaryotic protein degradation via the ubiquitin (Ub) proteasome system (UPS) [1,2]. In mammals the core complex consists of 8 subunits (CSN1 to CSN8) [3], the exact function of which is not exactly known. CSN5 exhibits a MPN+/JAMM domain [4,5] responsible for metalloprotease activity. As a complex-bound protein CSN5 removes NEDD8, an ubiquitin-like protein, from cullins. This cleavage of an isopeptide bond called deneddylation controls the ubiquitination by cullin-RING Ub ligases (CRLs), a large family of multisubunit E3s [6,7]. Cullin proteins (Cul1 to Cul7) are components of CRLs functioning as scaffolds of the Ub ligase complexes. Cullin neddylation and den
Conservation of the COP9/signalosome in budding yeast
Susan Wee, Bettina Hetfeld, Wolfgang Dubiel, Dieter A Wolf
BMC Genetics , 2002, DOI: 10.1186/1471-2156-3-15
Abstract: We show that disruption of four budding yeast genes, PCI8 and three previously uncharacterized ORFs, which encode proteins interacting with Rrr1p/Csn5p, each results in the accumulation of the cullin Cdc53p exclusively in the Rub1p-modified state. This phenotype, which resembles that of fission yeast csn mutants, is due to a biochemical defect in deneddylation that is complemented by wild-type cell lysate and by purified human CSN in vitro. Although three of the four genes encode proteins with PCI domains conserved in metazoan CSN proteins, their disruption does not confer the DNA damage sensitivity described in some fission yeast csn mutants.Our studies present unexpected evidence for the conservation of a functional homologue of the metazoan CSN, which mediates control of cullin neddylation in budding yeast.The COP9/signalosome (CSN) was first identified in Arabidopsis thaliana as an eight subunit complex involved in the suppression of light-dependent development [1]. Subsequent studies have led to the identification of similar complexes in other plant species, Drosophila melanogaster, human cells, and fission yeast [2-7], thus indicating a high degree of structural conservation during evolution. Cloning of CSN subunits revealed their structural similarities to the eight subunits of the lid complex of the 26S proteasome [3,8-10]. The similarity was most pronounced within the so-called MPN domains of CSN5 and 6 and the PCI domains of the remaining subunits [11].CSN has been implicated in multiple biological processes, many involving ubiquitin-mediated proteolysis (reviewed in [12,13]). For example, CSN is required for degradation of the plant transcription factor HY5 by the putative COP1 ubiquitin ligase [14]. In addition, CSN is involved in auxin-induced turn-over of the transcriptional repressor AUX/IAA [15]. This process is mediated by an ubiquitin ligase [15] related to SCF complexes first identified in budding yeast [16,17]. All SCF complexes share the core su
Novel curcumin- and emodin-related compounds identified by in silico 2D/3D conformer screening induce apoptosis in tumor cells
Melanie Füllbeck, Xiaohua Huang, Renate Dumdey, Cornelius Frommel, Wolfgang Dubiel, Robert Preissner
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-97
Abstract: Here we present a novel method to identify efficient inhibitors of CSN-associated kinases. Using curcumin and emodin as lead structures an in silico screening with our in-house database containing more than 106 structures was carried out. Thirty-five compounds were identified and further evaluated by the Lipinski's rule-of-five. Two groups of compounds can be clearly discriminated according to their structures: the curcumin-group and the emodin-group. The compounds were evaluated in in vitro kinase assays and in cell culture experiments.The data revealed 3 compounds of the curcumin-group (e.g. piceatannol) and 4 of the emodin-group (e.g. anthrachinone) as potent inhibitors of CSN-associated kinases. Identified agents increased p53 levels and induced apoptosis in tumor cells as determined by annexin V-FITC binding, DNA fragmentation and caspase activity assays.Our data demonstrate that the new in silico screening method is highly efficient for identifying potential anti-tumor drugs.The COP9 signalosome (CSN), a conserved multimeric protein complex, functions at the interface between signal transduction and ubiquitin (Ub)-dependent proteolysis [1]. Because of associated enzymes, the CSN possesses kinase acitivity. Two of the associated kinases are the protein kinase CK2 (CK2) and the protein kinase D (PKD) [2]. More than 200 proteins are known to be phosphorylated by the CK2, which is located nearly everywhere in the cell. The PKD is a serine/threonine kinase localized at either the plasma membrane or the cytosol of lymphocytes [3] and is associated with very diverse cellular functions, including Golgi organization, plasma membrane directed transport, metastasis, immune response, apoptosis and cell proliferation [4]. It is assumed that the CSN is a platform that brings together the kinases and appropriate substrates [5]. Transcriptional regulators such as p53 and c-Jun are phosphorylated by the CSN kinases [6,7]. The phosphorylation of p53 at Thr155 results in Ub-depe
Normal Functions as a New Way of Defining Computable Functions
Leszek Dubiel
Computer Science , 2004,
Abstract: Report sets new method of defining computable functions. This is formalization of traditional function descriptions, so it allows to define functions in very intuitive way. Discovery of Ackermann function proved that not all functions that can be easily computed can be so easily described with Hilbert's system of recursive functions. Normal functions lack this disadvantage.
Generating Turing Machines by Use of Other Computation Models
Leszek Dubiel
Computer Science , 2003,
Abstract: For each problem that can be solved there exists algorithm, which can be described with a program of Turing machine. Because this is very simple model programs tend to be very complicated and hard to analyse by human. The best practice to solve given type of problems is to define a new model of computation that allows for quick and easy programming, and then to emulate its operation with Turing machine. This article shows how to define most suitable model for computation on natural numbers and defines Turing machine that emulates its operation.
Promoting target models by potential measures
Joerg Dubiel
Statistics , 2010,
Abstract: Direct marketers use target models in order to minimize the spreading loss of sales efforts. The application of target models has become more widespread with the increasing range of sales efforts. Target models are relevant for offline marketers sending printed mails as well as for online marketers who have to avoid intensity. However business has retained its evaluation since the late 1960s. Marketing decision-makers still prefer managerial performance measures of the economic benefit of a target model. Such benefit measures have merits but are unfavorable in other respects: They constrain leadership by stretched targets since they do not tell us how good a model could be. And they require a predisposed decision regarding cut-offs. Since this is based on earlier optimizations it virtually means sticking to traditions. Hence it is recommended also to use cut-off invariant and potential oriented performance measures for the model evaluation. This has three advantages: sustaining stretched targets, identifying improvement potential and sup-porting an automated evaluation of many different models. This article introduces a concrete po-tential measure and shows how to calculate it. It is especially recommended for direct marketing businesses churning out many specific target models at short intervals.
Dose dependent role of Emodin and BTB14431 in suspension colon cancer model in rats
Stephan Rogalla,Jana Pohlenz,Vanessa Garcia,Gerold Koplin,Kirsten Fuehrer,Andreas Lun,Wolfgang Dubiel,Caroline F. Geier,Chris Braumann
PeerJ , 2015, DOI: 10.7287/peerj.preprints.304v1
Abstract: Background. An “In Silico 2D/3D Conformer Screening” for structural similar antitumor substances to Curcumin was carried out and the novel antrachinone BTB14431 was found. Emodin, contained in several Chinese medical plants and BTB14431 are known to be potential inhibitors of the COP9-signalosome - stabilizing the tumor suppressor protein p53. The aim of this study was to analyze the suppressing effects on colorectal cancer in a standardized rat model (WAG/Rij).
Control of Multicellular Development by the Physically Interacting Deneddylases DEN1/DenA and COP9 Signalosome
Martin Christmann equal contributor,Tilo Schmaler equal contributor,Colin Gordon,Xiaohua Huang,?zgür Bayram,Josua Schinke,Sina Stumpf,Wolfgang Dubiel ,Gerhard H. Braus
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003275
Abstract: Deneddylases remove the ubiquitin-like protein Nedd8 from modified proteins. An increased deneddylase activity has been associated with various human cancers. In contrast, we show here that a mutant strain of the model fungus Aspergillus nidulans deficient in two deneddylases is viable but can only grow as a filament and is highly impaired for multicellular development. The DEN1/DenA and the COP9 signalosome (CSN) deneddylases physically interact in A. nidulans as well as in human cells, and CSN targets DEN1/DenA for protein degradation. Fungal development responds to light and requires both deneddylases for an appropriate light reaction. In contrast to CSN, which is necessary for sexual development, DEN1/DenA is required for asexual development. The CSN-DEN1/DenA interaction that affects DEN1/DenA protein levels presumably balances cellular deneddylase activity. A deneddylase disequilibrium impairs multicellular development and suggests that control of deneddylase activity is important for multicellular development.
Relationship between the magnetic hyperfine field and the magnetic moment
S. M. Dubiel
Physics , 2008, DOI: 10.1016/j.jallcom.2009.08.101
Abstract: Based on experimental data it is shown, for some chosen alloys and compounds of iron, that there is no one unique relationship between the 57Fe-site magnetic hyperfine field, Bhf, and the magnetic moment per Fe atom, m. Instead, the Bhf-m plot consists of several branches, each of them being characteristic of a given alloy or compound. Consequently, the effective proportionality constant (hyperfine coupling constant) depends on the alloy system or compound, and for a given alloy system or compound it depends on the composition or even on the lattice site. Consequently, the scaling of Bhf into the underlying m cannot be done a priopri.
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