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Haitao Luan, Bhopal Mohapatra, Timothy A Bielecki, Insha Mushtaq, Sameer Mirza, Tameka A Jennings, Robert J Clubb, Wei An, Dena Ahmed, Rokaya El Ansari, Matthew D Storck, Nitish K Mishra, Chittibabu Guda, Yuri M Sheinin, Jane L Meza, Srikumar Raja, Emad A Rakha, Vimla Band, Hamid Band
CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two-thirds of ErbB2+ and triple-negative breast cancers and in one-third of ER+ breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2+ and triple-negative breast cancer cell lines...
March 6, 2018: Cancer Research
João Pedro de Magalhães, Louise Thompson, Izabella de Lima, Dale Gaskill, Xiaoyu Li, Daniel Thornton, Chenhao Yang, Daniel Palmer
Many studies have reported genetic interventions having an effect on mouse lifespan, however it is crucial to discriminate between manipulations of aging and aging-independent causes of life extension. Here, we used the Gompertz equation to determine whether previously reported aging-related mouse genes statistically affect the demographic rate of aging. Of 30 genetic manipulations previously reported to extend lifespan, for only 2 we found evidence of retarding demographic aging: Cisd2 and hMTH1 Of 24 genetic manipulations reported to shorten lifespan and induce premature aging features, we found evidence of 5 accelerating demographic aging: Casp2 , Fn1 , IKK-β , JunD and Stub1 Overall, our reassessment found that only 15% of the genetic manipulations analysed significantly affected the demographic rate of aging as predicted, suggesting that a relatively small proportion of interventions affecting longevity do so by regulating the rate of aging...
February 14, 2018: Genetics
Lang Rao, Youbao Sha, N Tony Eissa
TFEB is a master regulator for transcription of genes involved in autophagy, lysosome and mitochondrial biogenesis. Activity of TFEB is inhibited upon its phosphorylation. STUB1, a chaperone-dependent E3 ubiquitin ligase, modulates TFEB activity by preferentially targeting inactive phosphorylated TFEB for degradation by the ubiquitin proteasome pathway. Thus, the ubiquitin-proteasome pathway participates in regulating autophagy and lysosomal functions by regulating the activity of TFEB.
2017: Molecular & Cellular Oncology
Mark J Ranek, Marisa J Stachowski, Jonathan A Kirk, Monte S Willis
The ongoing contractile and metabolic demands of the heart require a tight control over protein quality control, including the maintenance of protein folding, turnover and synthesis. In heart disease, increases in mechanical and oxidative stresses, post-translational modifications (e.g., phosphorylation), for example, decrease protein stability to favour misfolding in myocardial infarction, heart failure or ageing. These misfolded proteins are toxic to cardiomyocytes, directly contributing to the common accumulation found in human heart failure...
January 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Moshe Shashar, Mostafa E Belghasem, Shinobu Matsuura, Joshua Walker, Sean Richards, Faisal Alousi, Keshab Rijal, Vijaya B Kolachalama, Mercedes Balcells, Minami Odagi, Kazuo Nagasawa, Joel M Henderson, Amitabh Gautam, Richard Rushmore, Jean Francis, Daniel Kirchhofer, Kumaran Kolandaivelu, David H Sherr, Elazer R Edelman, Katya Ravid, Vipul C Chitalia
Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute-specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner...
November 22, 2017: Science Translational Medicine
Lin Hu, Jiafeng Xu, Xiaomei Xie, Yiwen Zhou, Panfeng Tao, Haidong Li, Xu Han, Chong Wang, Jian Liu, Pinglong Xu, Dante Neculai, Zongping Xia
Ubiquitin ligase TRAF6, together with ubiquitin-conjugating enzyme Ubc13/Uev1, catalyzes processive assembly of unanchored K63-linked polyubiquitin chains for TAK1 activation in the IL-1R/TLR pathways. However, what domain and how it functions to enable TRAF6's processivity are largely uncharacterized. Here, we find TRAF6 coiled-coil (CC) domain is crucial to enable its processivity. The CC domain mediates TRAF6 oligomerization to ensure efficient long polyubiquitin chain assembly. Mutating or deleting the CC domain impairs TRAF6 oligomerization and processive polyubiquitin chain assembly...
October 9, 2017: Nature Communications
Youbao Sha, Lang Rao, Carmine Settembre, Andrea Ballabio, N Tony Eissa
TFEB is a master regulator for transcription of genes involved in autophagy and lysosome biogenesis. Activity of TFEB is inhibited upon its serine phosphorylation by mTOR The overall mechanisms by which TFEB activity in the cell is regulated are not well elucidated. Specifically, the mechanisms of TFEB turnover and how they might influence its activity remain unknown. Here, we show that STUB1, a chaperone-dependent E3 ubiquitin ligase, modulates TFEB activity by preferentially targeting inactive phosphorylated TFEB for degradation by the ubiquitin-proteasome pathway...
September 1, 2017: EMBO Journal
Kazuya Tsubouchi, Jun Araya, Shunsuke Minagawa, Hiromichi Hara, Akihiro Ichikawa, Nayuta Saito, Tsukasa Kadota, Nahoko Sato, Masahiro Yoshida, Yusuke Kurita, Kenji Kobayashi, Saburo Ito, Yu Fujita, Hirofumi Utsumi, Haruhiko Yanagisawa, Mitsuo Hashimoto, Hiroshi Wakui, Yutaka Yoshii, Takeo Ishikawa, Takanori Numata, Yumi Kaneko, Hisatoshi Asano, Makoto Yamashita, Makoto Odaka, Toshiaki Morikawa, Katsutoshi Nakayama, Yoichi Nakanishi, Kazuyoshi Kuwano
Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF) pathogenesis. TGFB (transforming growth factor β) is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 (NADPH oxidase 4) has an essential role in TGFB-mediated cell signaling. Azithromycin (AZM), a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung fibrosis development...
August 3, 2017: Autophagy
Z Cao, S L Zheng, G Yang, M Y Feng, L F Zheng, T P Zhang, Y P Zhao
Objective: To test the expression of miR-1178 in pancreatic cancer and study its clinicopathological significance and mechanism. Methods: The expression of miR-1178 in 87 paired paraffin pancreatic ductal adenocarcinoma specimens and adjacent non- cancerous pancreatic tissue diagnosed by Pathology Department of Peking Union Medical College Hospital was detected by hybridization in situ. The relationship between the expression of miR-1178 and clinicopathological characters was analyzed.miR-1178 mimics and inhibitor were used to further detect the close relationship among miR-1178 and cancer invasion...
June 1, 2017: Zhonghua Wai Ke za Zhi [Chinese Journal of Surgery]
Taishi Yonezawa, Hirotaka Takahashi, Shiori Shikata, Xiaoxiao Liu, Moe Tamura, Shuhei Asada, Tsuyoshi Fukushima, Tomofusa Fukuyama, Yosuke Tanaka, Tatsuya Sawasaki, Toshio Kitamura, Susumu Goyama
RUNX1 is a member of RUNX transcription factors and plays important roles in hematopoiesis. Disruption of RUNX1 activity has been implicated in the development of hematopoietic neoplasms. Chromosomal translocations involving the RUNX1 gene are associated with several types of leukemia, including acute myeloid leukemia driven by a leukemogenic fusion protein RUNX1-RUNX1T1. Previous studies have shown that RUNX1 is an unstable protein and is subjected to proteolytic degradation mediated by the ubiquitin-proteasome pathway...
July 28, 2017: Journal of Biological Chemistry
Sukumar Sarkar, David L Brautigan, James M Larner
Reducing the levels of the androgen receptor (AR) is one of the most viable approaches to combat castration-resistant prostate cancer. Previously, we observed that proteasomal-dependent degradation of AR in response to 2-methoxyestradiol (2-ME) depends primarily on the E3 ligase C-terminus of HSP70-interacting protein (STUB1/CHIP). Here, 2-ME stimulation activates CHIP by phosphorylation via Aurora kinase A (AURKA). Aurora A kinase inhibitors and RNAi knockdown of Aurora A transcript selectively blocked CHIP phosphorylation and AR degradation...
August 2017: Molecular Cancer Research: MCR
Marie Coutelier, Giulia Coarelli, Marie-Lorraine Monin, Juliette Konop, Claire-Sophie Davoine, Christelle Tesson, Rémi Valter, Mathieu Anheim, Anthony Behin, Giovanni Castelnovo, Perrine Charles, Albert David, Claire Ewenczyk, Mélanie Fradin, Cyril Goizet, Didier Hannequin, Pierre Labauge, Florence Riant, Pierre Sarda, Yves Sznajer, François Tison, Urielle Ullmann, Lionel Van Maldergem, Fanny Mochel, Alexis Brice, Giovanni Stevanin, Alexandra Durr
Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype-phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more 'conventional' ataxias...
June 1, 2017: Brain: a Journal of Neurology
Yasaman Pakdaman, Monica Sanchez-Guixé, Rune Kleppe, Sigrid Erdal, Helene J Bustad, Lise Bjørkhaug, Kristoffer Haugarvoll, Charalampos Tzoulis, Ketil Heimdal, Per M Knappskog, Stefan Johansson, Ingvild Aukrust
Spinocerebellar ataxia, autosomal recessive 16 (SCAR16) is caused by biallelic mutations in the STIP1 homology and U-box containing protein 1 (STUB1) gene encoding the ubiquitin E3 ligase and dimeric co-chaperone C-terminus of Hsc70-interacting protein (CHIP). It has been proposed that the disease mechanism is related to CHIP's impaired E3 ubiquitin ligase properties and/or interaction with its chaperones. However, there is limited knowledge on how these mutations affect the stability, folding, and protein structure of CHIP itself...
April 30, 2017: Bioscience Reports
Y Shang, J He, Y Wang, Q Feng, Y Zhang, J Guo, J Li, S Li, Y Wang, G Yan, F Ren, Y Shi, J Xu, N Zeps, Y Zhai, D He, Z Chang
Tumor cells preferentially adopt aerobic glycolysis for their energy supply, a phenomenon known as the Warburg effect. It remains a matter of debate as to how the Warburg effect is regulated during tumor progression. Here, we show that CHIP (carboxyl terminus of Hsc70-interacting protein), a U-box E3 ligase, suppresses tumor progression in ovarian carcinomas by inhibiting aerobic glycolysis. While CHIP is downregulated in ovarian carcinoma, induced expression of CHIP results in significant inhibition of the tumor growth examined by in vitro and in vivo experiments...
July 20, 2017: Oncogene
Weifeng Han, Lei Chen, Junpeng Liu, Ai Guo
The carboxyl terminus of Hsc70-interacting protein (CHIP, also known as STUB1) plays critical roles in the proliferation and differentiation of many types of cells. The potential function of CHIP in tendon-derived stem cells (TDSCs) remains largely unknown at present. Here, we investigated the effects of CHIP on tenogenic differentiation of TDSCs via lentivirus-mediated overexpression. Forced expression of CHIP induced morphological changes and significantly enhanced cell proliferation, as well as tendon differentiation in vitro...
April 1, 2017: Acta Biochimica et Biophysica Sinica
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 current 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(s) and used coimmunoprecipitation to verify the endogenous protein interaction...
July 15, 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
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