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Stefanie Nicole Hayer, Tine Deconinck, Benjamin Bender, Katrien Smets, Stephan Züchner, Selina Reich, Ludger Schöls, Rebecca Schüle, Peter De Jonghe, Jonathan Baets, Matthis Synofzik
BACKGROUND: CHIP, the protein encoded by STUB1, is a central component of cellular protein homeostasis and interacts with several key proteins involved in the pathogenesis of manifold neurodegenerative diseases. This gives rise to the hypothesis that mutations in STUB1 might cause a far more multisystemic neurodegenerative phenotype than the previously reported cerebellar ataxia syndrome. METHODS: Whole exome sequencing data-sets from n = 87 index subjects of two ataxia cohorts were screened for individuals with STUB1 mutations...
February 13, 2017: Orphanet Journal of Rare Diseases
Zhaojing Wang, Yufeng Hu, Daibiao Xiao, Jingchao Wang, Chuntao Liu, Yisheng Xu, Xiaomeng Shi, Peng Jiang, Liang Huang, Peng Li, Hudan Liu, Guoliang Qing
PURPOSE: Notch1 deregulation is assuming a focal role in T-cell acute lymphoblastic leukemia (T-ALL). Despite tremendous advances in our understanding of Notch1 transcriptional programs, the mechanisms by which Notch1 stability and turnover are regulated remain obscure. The goal of the present study is to identify intracellular Notch1 (ICN1, the activated form of Notch1) binding partner(s) regulating its stability and activity. EXPERIMENTAL DESIGN: We employed immunoaffinity purification to identify ICN1-associating partner and used co-immunoprecipitation to verify the endogenous protein interaction...
January 31, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Bianca Schönbühler, Verena Schmitt, Heike Huesmann, Andreas Kern, Martin Gamerdinger, Christian Behl
The maintenance of cellular proteostasis is dependent on molecular chaperones and protein degradation pathways. Chaperones facilitate protein folding, maturation, and degradation, and the particular fate of a misfolded protein is determined by the interaction of chaperones with co-chaperones. The co-factor CHIP (C-terminus of HSP70-inteacting protein, STUB1) ubiquitinates chaperone substrates and directs proteins to the cellular degradation systems. The activity of CHIP is regulated by two co-chaperones, BAG2 and HSPBP1, which are potent inhibitors of the E3 ubiquitin ligase activity...
December 30, 2016: International Journal of Molecular Sciences
Adolfo M García, Sofía Abrevaya, Giselle Kozono, Indira García Cordero, Marta Córdoba, Marcelo Andrés Kauffman, Ricardo Pautassi, Edinson Muñoz, Lucas Sedeño, Agustín Ibáñez
No abstract text is available yet for this article.
February 2017: Journal of Medical Genetics
Nifang Niu, Tongzheng Liu, Junmei Cairns, Reynold C Ly, Xianglin Tan, Min Deng, Brooke L Fridley, Krishna R Kalari, Ryan P Abo, Gregory Jenkins, Anthony Batzler, Erin E Carlson, Poulami Barman, Sebastian Moran, Holger Heyn, Manel Esteller, Liewei Wang
Metformin is currently considered as a promising anticancer agent in addition to its anti-diabetic effect. To better individualize metformin therapy and explore novel molecular mechanisms in cancer treatment, we conducted a pharmacogenomic study using 266 lymphoblastoid cell lines (LCLs). Metformin cytotoxicity assay was performed using the MTS assay. Genome-wide association (GWA) analyses were performed in LCLs using 1.3 million SNPs, 485k DNA methylation probes, 54k mRNA expression probe sets, and metformin cytotoxicity (IC50s)...
September 11, 2016: Human Molecular Genetics
Miao Wang, Xingyuan Xiao, Fuqing Zeng, Fei Xie, Yebin Fan, Chao Huang, Guosong Jiang, Liang Wang
Our study aimed to explore long non-coding RNAs (lncRNAs) contributing to the development of bladder cancer, as well as to identify more critical DEGs and lncRNAs that would characterize low- and high-grade bladder cancer. The microarray data of GSE55433 was downloaded from Gene Expression Omnibus database, including 57 urothelial cancer samples (23 low-grade NMI, 14 high-grade NMI and 20 invasive tumors) and 26 normal controls. The differentially expressed genes (DEGs) and differentially expressed lncRNAs were identified in 3 groups (low-grade NMI vs...
October 30, 2016: Gene
Dolores Del Prete, Richard C Rice, Anjali M Rajadhyaksha, Luciano D'Adamio
The amyloid precursor protein (APP), whose mutations cause Alzheimer disease, plays an important in vivo role and facilitates transmitter release. Because the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that the ACR interacts with proteins that regulate the ubiquitin-proteasome system, predominantly with the E3 ubiquitin-protein ligases Stub1, which binds the NH2 terminus of the ACR, and CRL4(CRBN), which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn...
August 12, 2016: Journal of Biological Chemistry
Yizhi Zhang, Zhoujia Chen, Xuerui Luo, Bin Wu, Bin Li, Bin Wang
Foxp3-expressing Treg cells have been well documented to provide immune regulation by promoting immune tolerance and suppressing immune over-reaction. Cimetidine (CIM), used to inhibit stomach acid secretion, has been reported to promote immune responses and suppress Treg cell function in several studies. However, the underlying mechanism is unknown. To investigate CIM effects on the suppressive function of Treg and Foxp3, here we used CIM to stimulate human CD4(+)CD25(+) Treg cells and Jurkat T cells and evaluated changes of Foxp3 expression and stability...
October 2, 2016: Human Vaccines & Immunotherapeutics
Yu Guo, Ming Zhao, Qianjin Lu
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease caused by complex interactions between genes and the environment. The expression level of transcription factor regulatory factor X 1 (RFX1) is reduced in T cells from SLE patients. RFX1 can regulate epigenetic modifications of CD70 and CD11a and plays an important role in the development of SLE. However, the mechanisms that mediate reduction of RFX1 in SLE are unclear. Here, we demonstrate that RFX1 protein expression can be tightly regulated by polyubiquitination-mediated proteosomal degradation via STIP1 homology and U-box containing protein 1 (STUB1)...
August 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Barbara Medvar, Viswanathan Raghuram, Trairak Pisitkun, Abhijit Sarkar, Mark A Knepper
Aquaporin-2 (AQP2) is regulated in part via vasopressin-mediated changes in protein half-life that are in turn dependent on AQP2 ubiquitination. Here we addressed the question, "What E3 ubiquitin ligase is most likely to be responsible for AQP2 ubiquitination?" using large-scale data integration based on Bayes' rule. The first step was to bioinformatically identify all E3 ligase genes coded by the human genome. The 377 E3 ubiquitin ligases identified in the human genome, consisting predominant of HECT, RING, and U-box proteins, have been used to create a publically accessible and downloadable online database (https://hpcwebapps...
July 1, 2016: Physiological Genomics
Fuying Xue, Yanping Wu, Xinghui Zhao, Taoran Zhao, Ying Meng, Zhanzhong Zhao, Junwei Guo, Wei Chen
Nucleobindin-1 (NUCB1), also known as Calnuc, is a highly conserved, multifunctional protein widely expressed in tissues and cells. It contains two EF-hand motifs which have been shown to play a crucial role in binding Ca(2+) ions. In this study, we applied comparative two-dimensional gel electrophoresis to characterize differentially expressed proteins in HA-CHIP over-expressed and endogenous CHIP depleted MC3T3-E1 stable cell lines, identifying NUCB1 as a novel CHIP/Stub1 targeted protein. NUCB1 interacts with and is down-regulated by CHIP by both proteasomal dependent and independent pathways, suggesting that CHIP-mediated down-regulation of nucleobindin-1 might play a role in osteoblast differentiation...
2016: Cellular Signalling
Hazem Ahmed, Shili Duan, Cheryl H Arrowsmith, Dalia Barsyte-Lovejoy, Matthieu Schapira
Protein methylation is a post-translational modification with important roles in transcriptional regulation and other biological processes, but the enzyme-substrate relationship between the 68 known human protein methyltransferases and the thousands of reported methylation sites is poorly understood. Here, we propose a bioinformatic approach that integrates structural, biochemical, cellular, and proteomic data to identify novel cellular substrates of the lysine methyltransferase SMYD2. Of the 14 novel putative SMYD2 substrates identified by our approach, six were confirmed in cells by immunoprecipitation: MAPT, CCAR2, EEF2, NCOA3, STUB1, and UTP14A...
June 3, 2016: Journal of Proteome Research
Jinho Seo, Eun-Woo Lee, Hyerim Sung, Daehyeon Seong, Yves Dondelinger, Jihye Shin, Manhyung Jeong, Hae-Kyung Lee, Jung-Hoon Kim, Su Yeon Han, Cheolju Lee, Je Kyung Seong, Peter Vandenabeele, Jaewhan Song
Receptor-interacting protein kinase 3 (RIPK3) functions as a key regulator of necroptosis. Here, we report that the RIPK3 expression level is negatively regulated by CHIP (carboxyl terminus of Hsp70-interacting protein; also known as STUB1) E3 ligase-mediated ubiquitylation. Chip(-/-) mouse embryonic fibroblasts and CHIP-depleted L929 and HT-29 cells exhibited higher levels of RIPK3 expression, resulting in increased sensitivity to necroptosis induced by TNF (also known as TNFα). These phenomena are due to the CHIP-mediated ubiquitylation of RIPK3, which leads to its lysosomal degradation...
March 2016: Nature Cell Biology
Aline Ketefian, Michelle R Jones, Ronald M Krauss, Yii-Der I Chen, Richard S Legro, Ricardo Azziz, Mark O Goodarzi
OBJECTIVE: To evaluate genes involved in androgen receptor (AR) signaling as candidate genes for polycystic ovary syndrome (PCOS). DESIGN: Two groups of women with PCOS and control women (discovery and replication cohorts), were genotyped for single-nucleotide polymorphisms (SNPs) in eight genes for AR chaperones and co-chaperones: HSPA1A, HSPA8, ST13, STIP1, PTGES3, FKBP4, BAG1, and STUB1. Single-nucleotide polymorphisms were tested for association with PCOS status and with androgenic and metabolic parameters...
February 2016: Fertility and Sterility
Marta F Bustamante, Carlos Morcillo-Suárez, Sunny Malhotra, Jordi Rio, Laura Leyva, Oscar Fernández, Uwe K Zettl, Joep Killestein, David Brassat, Juan Antonio García-Merino, Antonio J Sánchez, Elena Urcelay, Roberto Alvarez-Lafuente, Lusia M Villar, Jose Carlos Alvarez-Cermeño, Xavier Farré, Jeannette Lechner-Scott, Koen Vandenbroeck, Alfredo Rodríguez-Antigüedad, Jelena S Drulovic, Filippo Martinelli Boneschi, Andrew Chan, Jorge Oksenberg, Arcadi Navarro, Xavier Montalban, Manuel Comabella
OBJECTIVES: We aimed to investigate the association between polymorphisms located in type I interferon (IFN)-induced genes, genes belonging to the toll-like receptor (TLR) pathway, and genes encoding neurotransmitter receptors and the response to IFN-β treatment in patients with multiple sclerosis (MS). METHODS: In a first or screening phase of the study, 384 polymorphisms were genotyped in 830 patients with MS classified into IFN-β responders (n = 416) and nonresponders (n = 414) according to clinical criteria...
October 2015: Neurology® Neuroimmunology & Neuroinflammation
Parvez Syed, Shabarni Gupta, Saket Choudhary, Narendra Goud Pandala, Apurva Atak, Annie Richharia, Manubhai K P, Heng Zhu, Sridhar Epari, Santosh B Noronha, Aliasgar Moiyadi, Sanjeeva Srivastava
The heterogeneity and poor prognosis associated with gliomas, makes biomarker identification imperative. Here, we report autoantibody signatures across various grades of glioma serum samples and sub-categories of glioblastoma multiforme using Human Proteome chips containing ~17000 full-length human proteins. The deduced sets of classifier proteins helped to distinguish Grade II, III and IV samples from the healthy subjects with 88, 89 and 94% sensitivity and 87, 100 and 73% specificity, respectively. Proteins namely, SNX1, EYA1, PQBP1 and IGHG1 showed dysregulation across various grades...
2015: Scientific Reports
Georgios D Vavougios, Evgeniy I Solenov, Chrissi Hatzoglou, Galina S Baturina, Liubov E Katkova, Paschalis Adam Molyvdas, Konstantinos I Gourgoulianis, Sotirios G Zarogiannis
The aim of our study was to assess the differential gene expression of Parkinson protein 7 (PARK7) interactome in malignant pleural mesothelioma (MPM) using data mining techniques to identify novel candidate genes that may play a role in the pathogenicity of MPM. We constructed the PARK7 interactome using the ConsensusPathDB database. We then interrogated the Oncomine Cancer Microarray database using the Gordon Mesothelioma Study, for differential gene expression of the PARK7 interactome. In ConsensusPathDB, 38 protein interactors of PARK7 were identified...
October 1, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
Ana Paula Lappas Gimenez, Larissa Morato Luciani Richter, Mariana Campos Atherino, Breno Castello Branco Beirão, Celso Fávaro, Michele Dietrich Moura Costa, Silvio Marques Zanata, Bettina Malnic, Adriana Frohlich Mercadante
Prion diseases involve the conversion of the endogenous cellular prion protein, PrP(C), into a misfolded infectious isoform, PrP(Sc). Several functions have been attributed to PrP(C), and its role has also been investigated in the olfactory system. PrP(C) is expressed in both the olfactory bulb (OB) and olfactory epithelium (OE) and the nasal cavity is an important route of transmission of diseases caused by prions. Moreover, Prnp(-/-) mice showed impaired behavior in olfactory tests. Given the high PrP(C) expression in OE and its putative role in olfaction, we screened a mouse OE cDNA library to identify novel PrP(C)-binding partners...
2015: Prion
Dongkai Guo, Zheng Ying, Hongfeng Wang, Dong Chen, Feng Gao, Haigang Ren, Guanghui Wang
Autophagy is a major degradation system which processes substrates through the steps of autophagosome formation, autophagosome-lysosome fusion, and substrate degradation. Aberrant autophagic flux is present in many pathological conditions including neurodegeneration and tumors. CHIP/STUB1, an E3 ligase, plays an important role in neurodegeneration. In this study, we identified the regulation of autophagic flux by CHIP (carboxy-terminus of Hsc70-interacting protein). Knockdown of CHIP induced autophagosome formation through increasing the PTEN protein level and decreasing the AKT/mTOR activity as well as decreasing phosphorylation of ULK1 on Ser757...
August 2015: Neuroscience Bulletin
Xiao-Rui Cheng, Xiu-Liang Cui, Yue Zheng, Gui-Rong Zhang, Peng Li, Huang Huang, Yue-Ying Zhao, Xiao-Chen Bo, Sheng-Qi Wang, Wen-Xia Zhou, Yong-Xiang Zhang
There are currently no approved effective therapies for Alzheimer's disease (AD). AD is a classic, multifactorial, complex syndrome. Thus, a polypharmacological or multitargeted approach to AD might provide better therapeutic benefits than monotherapies. However, it remains elusive which biological processes and biomolecules involved in the pathophysiologic processes of AD would constitute good targets for multitargeted therapy. This study proposes that a co-module, consisting of biological processes, cellular pathways and nodes, in a molecular subnetwork perturbed by different therapeutic drugs may be the optimal therapeutic target for an AD multitarget-based intervention...
2015: Current Alzheimer Research
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