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https://www.readbyqxmd.com/read/29033641/do-low-serum-uch-l1-and-tdp-43-levels-indicate-disturbed-ubiquitin-proteosome-system-in-autism-spectrum-disorder
#1
İhsan Çetin, İhsan Tezdiğ, Mahmut Cem Tarakçioğlu, Muhammed Tayyib Kadak, Ömer Faruk Demirel, Ömer Faruk Özer, Fırat Erdoğan, Burak Doğangün
INTRODUCTION: The mechanism of ubiquitination-related abnormalities causing neural development problems is still unclear. We examined the association between autism and serum transactive response DNA-binding protein-43 (TDP-43) and ubiquitin c-terminal hydrolase-L1 (UCH-L1) levels, both of which are members of the ubiquitin-proteosome system. METHODS: We measured serum levels of TDP-43 and UCH-L1 in 24 children with autism and 24 healthy children. Childhood Autism Rating Scale (CARS) was used to assess symptom severity at admission...
September 2017: Noro Psikiyatri Arsivi
https://www.readbyqxmd.com/read/29021293/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 H K Lim, Alan P Kumar
Metastatic breast cancer is still 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 have 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 that model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and PPARγ...
August 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28981589/notch-activation-by-shootin1-opposing-activities-on-2-ubiquitin-ligases
#3
Tamar Sapir, Talia Levy, Noga Kozer, Irina Shin, Vanessa Zamor, Rebecca Haffner-Krausz, Jane C McGlade, Orly Reiner
The evolutionarily conserved Notch pathway plays an important role in regulation of stem cell renewal and cell fate determination in numerous organs, and as such is a key pathway in normal health and disease processes. Canonical Notch signaling is usually activated by cell contact where transmembrane ligands such as Delta-like and Jagged bind to Notch receptors. Notch activation results in the translocation of the cleaved Notch intracellular domain (NICD) into the nucleus and subsequent activation of transcription...
July 13, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28955980/crk-ii-silencing-down-regulates-igf-ir-and-inhibits-migration-and-invasion-of-prostate-cancer-cells
#4
Pooja Dhupkar, Huang Zhao, Kalpana Mujoo, Zhiqiang An, Ningyan Zhang
Crk (C10 regulator of kinase) adaptor proteins are highly expressed in many types of human cancers and often contribute to aggressive cancer phenotypes. Crk II, a member of CRK family, has been reported to regulate cell migration and metastasis in breast cancer cells. However, its role in other cancer types has not been reported. In this study, we investigated the molecular function of Crk II in prostate cancer (PCa) cells (CWR-22rv1) in vitro and using a mouse tumor model. Results showed that Crk II knockdown by shRNA-mediated silencing (Crk II-shRNA) in the PCa cells significantly inhibited both cancer cell migration and invasion in cell culture study...
December 2016: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/28947489/the-plastid-and-mitochondrial-peptidase-network-in-arabidopsis-thaliana-a-foundation-for-testing-genetic-interactions-and-functions-in-organellar-proteostasis
#5
Kristina Majsec, Nazmul H Bhuiyan, Qi Sun, Sunita Kumari, Vivek Kumar, Doreen Ware, Klaas Jan van Wijk
Plant plastids and mitochondria have dynamic proteomes. Protein homeostasis in these organelles is maintained by a proteostasis network containing protein chaperones, peptidases and their substrate recognition factors. However, many peptidases, as well as their functional connections and substrates, are poorly characterized. This review provides a systematic insight into the organellar peptidase network in Arabidopsis. We present a compendium of known and putative Arabidopsis peptidases and inhibitors, and compare the distribution of plastid and mitochondrial peptidases to the total peptidase complement...
September 25, 2017: Plant Cell
https://www.readbyqxmd.com/read/28943839/cellular-chaperones-as-therapeutic-targets-in-als-to-restore-protein-homeostasis-and-improve-cellular-function
#6
REVIEW
Bernadett Kalmar, Linda Greensmith
Heat shock proteins (Hsps) are ubiquitously expressed chaperone proteins that enable cells to cope with environmental stresses that cause misfolding and denaturation of proteins. With aging this protein quality control machinery becomes less effective, reducing the ability of cells to cope with damaging environmental stresses and disease-causing mutations. In neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS), such mutations are known to result in protein misfolding, which in turn results in the formation of intracellular aggregates cellular dysfunction and eventual neuronal death...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28943305/targeting-the-cancer-epigenome-synergistic-therapy-with-bromodomain-inhibitors
#7
REVIEW
Mahalakshmi Ramadoss, Vijayalakshmi Mahadevan
Epigenetic and genomic alterations regulate the transcriptional landscape of cells during cancer onset and progression. Recent clinical studies targeting the epigenetic 'readers' (bromodomains) for cancer therapy have established the effectiveness of bromodomain (BRD) extraterminal (BET) inhibitors in treating several types of cancer. In this review, we discuss key mechanisms of BET inhibition and synergistic combinations of BET inhibitors with histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), DNA methyltransferase inhibitors (DNMTi), kinase, B-cell lymphoma 2 (Bcl-2) and proteosome inhibitors, and immunomodulatory drugs for cancer therapy...
September 22, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28939210/toward-a-blood-borne-biomarker-of-chronic-hypoxemia-red-cell-distribution-width-and-respiratory-disease
#8
Joseph W Yčas
Hypoxemia (systemic oxygen desaturation) marks the presence, risk, and progression of many diseases. Episodic or nocturnal hypoxemia can be challenging to detect and quantify. A sensitive, specific, and convenient marker of recent oxygen desaturation represents an unmet medical need. Observations of acclimatization to high altitude in humans and animals reveals several proteosomic, ventilatory, and hematological responses to low oxygen tension. Of these, increased red cell distribution width (RDW) appears to have the longest persistence...
2017: Advances in Clinical Chemistry
https://www.readbyqxmd.com/read/28904177/limited-proteolysis-as-a-tool-to-probe-the-tertiary-conformation-of-dysferlin-and-structural-consequences-of-patient-missense-variant-l344p
#9
Natalie Woolger, Adam Bournazos, Reece A Sophocleous, Frances J Evesson, Angela Lek, Birgit Driemer, R Bryan Sutton, Sandra T Cooper
Dysferlin is a large transmembrane protein that plays a key role in cell membrane repair, and underlies a recessive form of inherited muscular dystrophy. Dysferlinopathy is characterized by absence or marked reduction of dysferlin protein, with 43% of reported pathogenic variants being missense variants that span the length of the dysferlin protein. The unique structure of dysferlin, with seven tandem C2-domains separated by linkers, suggest dysferlin may dynamically associate with phospholipid membranes in response to Ca2+ signaling...
September 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28881798/role-of-a-kinase-anchor-protein-akap4-in-growth-and-survival-of-ovarian-cancer-cells
#10
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)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28851829/glucocorticoids-promote-von-hippel-lindau-degradation-and-hif-1%C3%AE-stabilization
#11
Andrea Vettori, David Greenald, Garrick K Wilson, Margherita Peron, Nicola Facchinello, Eleanor Markham, Mathavan Sinnakaruppan, Laura C Matthews, Jane A McKeating, Francesco Argenton, Fredericus J M van Eeden
Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner...
September 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28826496/the-calcineurin-foxo-murf1-signaling-pathway-regulates-myofibril-integrity-in-cardiomyocytes
#12
Hirohito Shimizu, Adam D Langenbacher, Jie Huang, Kevin Wang, Georg Otto, Robert Geisler, Yibin Wang, Jau-Nian Chen
Altered Ca(2+) handling is often present in diseased hearts undergoing structural remodeling and functional deterioration. However, whether Ca(2+) directly regulates sarcomere structure has remained elusive. Using a zebrafish ncx1 mutant, we explored the impacts of impaired Ca(2+) homeostasis on myofibril integrity. We found that the E3 ubiquitin ligase murf1 is upregulated in ncx1-deficient hearts. Intriguingly, knocking down murf1 activity or inhibiting proteasome activity preserved myofibril integrity, revealing a MuRF1-mediated proteasome degradation mechanism that is activated in response to abnormal Ca(2+) homeostasis...
August 19, 2017: ELife
https://www.readbyqxmd.com/read/28812047/selected-missense-mutations-impair-frataxin-processing-in-friedreich-ataxia
#13
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
#14
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
#15
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
#16
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 29, 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
#17
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
#18
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
#19
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
#20
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
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