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https://www.readbyqxmd.com/read/28812047/selected-missense-mutations-impair-frataxin-processing-in-friedreich-ataxia
#1
Elisia Clark, Jill S Butler, Charles J Isaacs, Marek Napierala, David R Lynch
OBJECTIVE: Frataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease-related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing. METHODS: Immunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing...
August 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28811325/ppar%C3%AE-ligand-induced-annexin-a1-expression-determines-chemotherapy-response-via-deubiquitination-of-death-domain-kinase-rip-in-triple-negative-breast-cancers
#2
Luxi Chen, Yi Yuan, Shreya Kar, Madhu M Kanchi, Suruchi Arora, Ji E Kim, Pei F Koh, Einas Yousef, Ramar P Samy, Muthu K Shanmugam, Tuan Z Tan, Sung W Shin, Frank Arfuso, Han M Shen, Henry Yang, Boon C Goh, Joo I Park, Louis Gaboury, Peter E Lobie, Gautam Sethi, Lina Hk Lim, Alan P Kumar
Metastatic breast cancer is still remain incurable so far, new specifically targeted and more effective therapies for triple negative breast cancer (TNBC) are required in the clinic. In this study, our clinical data has established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines which model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and Peroxisome Proliferator-Activated Receptor gamma (PPARγ)...
August 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28765935/fbw7-increases-the-chemosensitivity-of-pancreatic-cancer-cells-to-gemcitabine-through-upregulation-of-ent1
#3
Qiangsheng Hu, Yi Qin, Bo Zhang, Chen Liang, Shunrong Ji, Si Shi, Wenyan Xu, Jinfeng Xiang, Dingkong Liang, Quanxing Ni, Xianjun Yu, Jin Xu
F-box and WD repeat domain-containing 7 (FBW7) has been characterized as a tumor suppressor, and its mutation or decreased expression has been observed in many types of human cancers. Our recent studies have uncovered that in pancreatic cancer, the KRAS mutation decreased FBW7 expression through phosphorylation and subsequent ubiquitination. Moreover, FBW7 inhibited aerobic glycolysis in pancreatic cancer via induction of thioredoxin-interacting protein (TXNIP), a mitochondrial localized tumor suppressor. The roles of FBW7 in anti-apoptosis and drug resistance via proteosomal degradation of myeloid cell leukemia-1 (MCL-1), which is an anti-apoptotic factor have been reported...
July 28, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28758396/impact-of-lca-associated-e14l-lrat-mutation-on-protein-stability-and-retinoid-homeostasis
#4
Sylwia Chelstowska, Made Airanthi K Widjaja-Adhi, Josie A Silvaroli, Marcin Golczak
Vitamin A (all-trans-retinol) is metabolized to the visual chromophore (11-cis-retinal) in the eyes and to all-trans-retinoic acid, a hormone like compound, in most tissues. A key enzyme in retinoid metabolism is lecithin:retinol acyltransferase (LRAT), which catalyzes the esterification of vitamin A. The importance of LRAT is indicated by pathogenic missense and nonsense mutations, which cause devastating blinding diseases. Retinoid-based chromophore replacement therapy has been proposed as treatment for these types of blindness based on studies in LRAT null mice...
August 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/28754303/type-i-ifn-and-not-tnf-is-essential-for-cyclic-di-nucleotide-elicited-ctl-by-a-cytosolic-cross-presentation-pathway
#5
Darío Lirussi, Thomas Ebensen, Kai Schulze, Stephanie Trittel, Veronica Duran, Ines Liebich, Ulrich Kalinke, Carlos A Guzmán
Cyclic di-nucleotides (CDN) are potent stimulators of innate and adaptive immune responses. Cyclic di-AMP (CDA) is a promising adjuvant that generates humoral and cellular immunity. The strong STING-dependent stimulation of type I IFN represents a key feature of CDA. However, recent studies suggested that this is dispensable for adjuvanticity. Here we demonstrate that stimulation of IFN-γ-secreting CD8(+) cytotoxic T lymphocytes (CTL) is significantly decreased after vaccination in the absence of type I IFN signaling...
August 2017: EBioMedicine
https://www.readbyqxmd.com/read/28751712/activation-of-mitophagy-leads-to-decline-in-mfn2-and-loss-of-mitochondrial-mass-in-fuchs-endothelial-corneal-dystrophy
#6
Anne-Sophie Benischke, Shivakumar Vasanth, Takashi Miyai, Kishore Reddy Katikireddy, Tomas White, Yuming Chen, Adna Halilovic, Marianne Price, Francis Price, Paloma B Liton, Ula V Jurkunas
Human corneal endothelial cells (HCEnCs) are terminally differentiated cells that have limited regenerative potential. The large numbers of mitochondria in HCEnCs are critical for pump and barrier function required for corneal hydration and transparency. Fuchs Endothelial Corneal Dystrophy (FECD) is a highly prevalent late-onset oxidative stress disorder characterized by progressive loss of HCEnCs. We previously reported increased mitochondrial fragmentation and reduced ATP and mtDNA copy number in FECD. Herein, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced mitochondrial depolarization decreased mitochondrial mass and Mfn2 levels, which were rescued with mitophagy blocker, bafilomycin, in FECD...
July 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28727686/fbxw7-regulates-disc1-stability-via-the-ubiquitin-proteosome-system
#7
K Yalla, C Elliott, J P Day, J Findlay, S Barratt, Z A Hughes, L Wilson, E Whiteley, M Popiolek, Y Li, J Dunlop, R Killick, D R Adams, N J Brandon, M D Houslay, B Hao, G S Baillie
Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7...
July 20, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28708669/the-role-of-hypothalamic-inflammation-the-hypothalamic-pituitary-adrenal-axis-and-serotonin-in-the-cancer-anorexia-cachexia-syndrome
#8
Klaske van Norren, Jvalini T Dwarkasing, Renger F Witkamp
PURPOSE OF REVIEW: In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia-cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. RECENT FINDINGS: The anorexia-cachexia syndrome is directly associated with higher mortality in cancer patients...
July 13, 2017: Current Opinion in Clinical Nutrition and Metabolic Care
https://www.readbyqxmd.com/read/28698388/delayed-cryptochrome-degradation-asymmetrically-alters-the-daily-rhythm-in-suprachiasmatic-clock-neuron-excitability
#9
Sven Wegner, Mino D C Belle, Alun T L Hughes, Casey O Diekman, Hugh D Piggins
Suprachiasmatic nuclei (SCN) neurons contain an intracellular molecular circadian clock and the Cryptochromes (CRY1/2), key transcriptional repressors of this molecular apparatus, are subject to post-translational modification through ubiquitination and targeting for proteosomal degradation by the ubiquitin E3 ligase complex. Loss-of-function point mutations in a component of this ligase complex, Fbxl3, delay CRY1/2 degradation, reduce circadian rhythm strength, and lengthen the circadian period by ∼2.5h...
July 11, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28691782/a-novel-microduplication-of-arid1b-clinical-genetic-and-proteomic-findings
#10
Catarina M Seabra, Nicholas Szoko, Serkan Erdin, Ashok Ragavendran, Alexei Stortchevoi, Patrícia Maciel, Kathleen Lundberg, Daniela Schlatzer, Janice Smith, Michael E Talkowski, James F Gusella, Marvin R Natowicz
Genetic alterations of ARID1B have been recently recognized as one of the most common mendelian causes of intellectual disability and are associated with both syndromic and non-syndromic phenotypes. The ARID1B protein, a subunit of the chromatin remodeling complex SWI/SNF-A, is involved in the regulation of transcription and multiple downstream cellular processes. We report here the clinical, genetic, and proteomic phenotypes of an individual with a unique apparent de novo mutation of ARID1B due to an intragenic duplication...
September 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28660894/proteostasis-in-cardiac-health-and-disease
#11
REVIEW
Robert H Henning, Bianca J J M Brundel
The incidence and prevalence of cardiac diseases, which are the main cause of death worldwide, are likely to increase because of population ageing. Prevailing theories about the mechanisms of ageing feature the gradual derailment of cellular protein homeostasis (proteostasis) and loss of protein quality control as central factors. In the heart, loss of protein patency, owing to flaws in genetically-determined design or because of environmentally-induced 'wear and tear', can overwhelm protein quality control, thereby triggering derailment of proteostasis and contributing to cardiac ageing...
June 29, 2017: Nature Reviews. Cardiology
https://www.readbyqxmd.com/read/28659470/hepatitis-c-virus-ns5a-targets-the-nucleosome-assembly-protein-nap1l1-to-control-the-innate-cellular-response
#12
Recep Emrah Çevik, Mia Cesarec, Ana Da Silva Filipe, Danilo Licastro, John McLauchlan, Alessandro Marcello
Hepatitis C virus (HCV) is a single-stranded positive-sense RNA hepatotropic virus. Despite cellular defenses, HCV is able to replicate in hepatocytes and to establish a chronic infection that could lead to severe complications and hepatocellular carcinoma. An important player in subverting the host response to HCV infection is the viral non-structural protein NS5A that, in addition to its role in replication and assembly, targets several pathways involved in the cellular response to viral infection. Several unbiased screens identified the nucleosome-assembly protein 1-like 1 (NAP1L1) as an interaction partner of HCV NS5A...
June 28, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28652134/effects-of-thermal-stress-on-the-expression-of-glucocorticoid-receptor-complex-linked-genes-in-senegalese-sole-solea-senegalensis-acute-and-adaptive-stress-responses
#13
Vanessa Benítez-Dorta, María J Caballero, Mónica B Betancor, Manuel Manchado, Lluis Tort, Silvia Torrecillas, María J Zamorano, Marisol Izquierdo, Daniel Montero
The present study examined the short and mid-term effects of a rise in temperature from 18°C to 24°C on the expression of genes related to the stress response regulation in juveniles of Senegalese sole, Solea senegalensis. The animals were exposed to a temperature increase of 6°C, after 1month of acclimation at 18°C. After this process, samples of different tissues were collected from a total of 96 fish at four sampling points: 1h, 24h, 3days and 1week. The transcript levels of a set of genes involved in the stress response such as glucocorticoid receptors 1 and 2, corticotrophin-releasing factor, corticotrophin-releasing factor binding proteins, proopiomelanocortin A and B, and cellular stress defense (heat shock protein 70, 90AA and 90AB) were quantified at these sampling points...
June 23, 2017: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/28631426/hsp90%C3%AE-regulates-atm-and-nbn-functions-in-sensing-and-repair-of-dna-double-strand-breaks
#14
EDITORIAL
Rosa Pennisi, Antonio Antoccia, Stefano Leone, Paolo Ascenzi, Alessandra di Masi
The molecular chaperone heat shock protein 90 (Hsp90α) regulates cell proteostasis and mitigates the harmful effects of endogenous and exogenous stressors on the proteome. Indeed, the inhibition of Hsp90α ATPase activity affects the cellular response to ionizing radiation (IR). Although the interplay between Hsp90α and several DNA damage response (DDR) proteins has been reported, its role in the DDR is still unclear. Here, we show that ataxia-telangiectasia-mutated kinase (ATM) and nibrin (NBN), but not 53BP1, RAD50, and MRE11, are Hsp90α clients as the Hsp90α inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) induces ATM and NBN polyubiquitination and proteosomal degradation in normal fibroblasts and lymphoblastoid cell lines...
August 2017: FEBS Journal
https://www.readbyqxmd.com/read/28604743/shortage-of-dntps-underlies-altered-replication-dynamics-and-dna-breakage-in-the-absence-of-the-apc-c-cofactor-cdh1
#15
J Garzón, R Rodríguez, Z Kong, A Chabes, S Rodríguez-Acebes, J Méndez, S Moreno, I García-Higuera
The APC/C-Cdh1 ubiquitin-ligase complex targets cell cycle regulators for proteosomal degradation and helps prevent tumor development and accumulation of chromosomal aberrations. Replication stress has been proposed to be the main driver of genomic instability in the absence of Cdh1, but the real contribution of APC/C-Cdh1 to efficient replication, especially in normal cells, remains unclear. Here we show that, in primary MEFs, acute depletion or permanent ablation of Cdh1 slowed down replication fork movement and increased origin activity...
June 12, 2017: Oncogene
https://www.readbyqxmd.com/read/28603485/multifaceted-mechanisms-of-wy-14643-to-stabilize-the-blood-brain-barrier-in-a-model-of-traumatic-brain-injury
#16
Winfried Neuhaus, Tobias Krämer, Anja Neuhoff, Christina Gölz, Serge C Thal, Carola Y Förster
The blood-brain barrier (BBB) is damaged during ischemic insults such as traumatic brain injury or stroke. This contributes to vasogenic edema formation and deteriorate disease outcomes. Enormous efforts are pursued to understand underlying mechanisms of ischemic insults and develop novel therapeutic strategies. In the present study the effects of PPARα agonist WY-14643 were investigated to prevent BBB breakdown and reduce edema formation. WY-14643 inhibited barrier damage in a mouse BBB in vitro model of traumatic brain injury based on oxygen/glucose deprivation in a concentration dependent manner...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28596494/role-of-a-kinase-anchor-protein-akap4-in-growth-and-survival-of-ovarian-cancer-cells
#17
Vikash Kumar, Nirmala Jagadish, Anil Suri
Ovarian cancer represents one of the most common malignancies among women with very high mortality rate worldwide. A-kinase anchor protein 4 (AKAP4), a unique cancer testis (CT) antigen has been shown to be associated with various malignant properties of cancer cells. However, its involvement in various molecular pathways in ovarian cancer remains unknown. In present investigation, employing gene silencing approach, we examined the role of AKAP4 in cell cycle, apoptosis and epithelial-mesenchymal transition (EMT)...
May 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28572574/survive-or-thrive-tradeoff-strategy-for-cellular-senescence
#18
REVIEW
Sang Chul Park
Aging-dependent cellular behaviors toward extrinsic stress are characterized by the confined localization of certain molecules to either nuclear or perinuclear regions. Although most growth factors can activate downstream signaling in aging cells, they do not in fact have any impact on the cells because the signals cannot reach their genetic targets in the nucleus. For the same reason, varying apoptotic stress factors cannot stimulate the apoptotic pathway in senescent cells. Thus, the operation of a functional nuclear barrier in an aging-dependent manner has been investigated...
June 2, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28562636/a-systematic-review-of-the-asymmetric-inheritance-of-cellular-organelles-in-eukaryotes-a-critique-of-basic-science-validity-and-imprecision
#19
Anne Collins, Janine Ross, Shona H Lang
We performed a systematic review to identify all original publications describing the asymmetric inheritance of cellular organelles in normal animal eukaryotic cells and to critique the validity and imprecision of the evidence. Searches were performed in Embase, MEDLINE and Pubmed up to November 2015. Screening of titles, abstracts and full papers was performed by two independent reviewers. Data extraction and validity were performed by one reviewer and checked by a second reviewer. Study quality was assessed using the SYRCLE risk of bias tool, for animal studies and by developing validity tools for the experimental model, organelle markers and imprecision...
2017: PloS One
https://www.readbyqxmd.com/read/28559853/proteogenomics-reveals-enriched-ribosome-assembly-and-protein-translation-in-pectoralis-major-of-high-feed-efficiency-pedigree-broiler-males
#20
Walter G Bottje, Kentu Lassiter, Alissa Piekarski-Welsher, Sami Dridi, Antonio Reverter, Nicholas J Hudson, Byung-Whi Kong
Background: In production animal agriculture, the cost of feed represents 60-70% of the total cost of raising an animal to market weight. Thus, development of viable biomarkers for feed efficiency (FE, g gain/g feed) to assist in genetic selection of breeding stock remains an important goal in commercial breeding programs. Methods: Global gene (cDNA microarray, RNAseq) and protein expression (shotgun proteomics) analyses have been conducted on breast muscle samples obtained from pedigree broiler males (PedM) exhibiting high and low FE phenotypes...
2017: Frontiers in Physiology
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