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https://www.readbyqxmd.com/read/28240313/enhancing-lysosomal-biogenesis-and-autophagic-flux-by-activating-the-transcription-factor-eb-protects-against-cadmium-induced-neurotoxicity
#1
Huifeng Pi, Min Li, Li Tian, Zhiqi Yang, Zhengping Yu, Zhou Zhou
Cadmium (Cd), a highly ubiquitous heavy metal, is a well-known inducer of neurotoxicity. However, the mechanism underlying cadmium-induced neurotoxicity remains unclear. In this study, we found that Cd inhibits autophagosome-lysosome fusion and impairs lysosomal function by reducing the levels of lysosomal-associated membrane proteins, inhibiting lysosomal proteolysis and altering lysosomal pH, contributing to defects in autophagic clearance and subsequently leading to nerve cell death. In addition, Cd decreases transcription factor EB (TFEB) expression at both the mRNA and protein levels...
February 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28237119/methods-to-monitor-and-manipulate-tfeb-activity-during-autophagy
#2
D L Medina, C Settembre, A Ballabio
Macroautophagy is a catabolic process deputed to the turnover of intracellular components. Recent studies have revealed that transcriptional regulation is a major mechanism controlling autophagy. Currently, more than 20 transcription factors have been shown to modulate cellular autophagy levels. Among them, the transcription factor EB (TFEB) appears to have the broadest proautophagy role, given its capacity to control the biogenesis of lysosomes and autophagosomes, the two main organelles required for the autophagy pathway...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28229902/impact-of-high-glucose-and-ages-on-cultured-kidney-derived-cells-effects-on-cell-viability-lysosomal-enzymes-and-effectors-of-cell-signaling-pathways
#3
Giovani B Peres, Nestor Schor, Yara M Michelacci
We have previously reported decreased expression and activities of lysosomal cathepsins B and L in diabetic kidney. Relevant morphological changes were observed in proximal tubules, suggesting that these cells are implicated in the early stages of the disease. The aim of the present study was to investigate the mechanisms that lead to these changes. The effects of high glucose (HG) and advanced glycation end products (AGEs) on cell viability, lysosomal enzymes and other effectors of cell signaling of cultured kidney cells were studied...
February 13, 2017: Biochimie
https://www.readbyqxmd.com/read/28187461/lysosomal-accumulation-of-anticancer-drugs-triggers-lysosomal-exocytosis
#4
Benny Zhitomirsky, Yehuda G Assaraf
We have recently shown that hydrophobic weak base anticancer drugs are highly sequestered in acidic lysosomes, inducing TFEB-mediated lysosomal biogenesis and markedly increased lysosome numbers per cell. This enhanced lysosomal sequestration of chemotherapeutics, away from their intracellular targets, provoked cancer multidrug resistance. However, little is known regarding the fate of lysosome-sequestered drugs. While we suggested that sequestered drugs might be expelled from cancer cells via lysosomal exocytosis, no actual drug-induced lysosomal exocytosis was demonstrated...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28165011/mtorc1-independent-tfeb-activation-via-akt-inhibition-promotes-cellular-clearance-in-neurodegenerative-storage-diseases
#5
Michela Palmieri, Rituraj Pal, Hemanth R Nelvagal, Parisa Lotfi, Gary R Stinnett, Michelle L Seymour, Arindam Chaudhury, Lakshya Bajaj, Vitaliy V Bondar, Laura Bremner, Usama Saleem, Dennis Y Tse, Deepthi Sanagasetti, Samuel M Wu, Joel R Neilson, Fred A Pereira, Robia G Pautler, George G Rodney, Jonathan D Cooper, Marco Sardiello
Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor...
February 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28154055/protected-from-atherosclerosis-by-tfeb
#6
EDITORIAL
Wei Wong
No abstract text is available yet for this article.
February 3, 2017: Science
https://www.readbyqxmd.com/read/28143906/new-connections-better-blood-vessels-and-muscles-with-tfeb
#7
Wei Wong
TFEB suppresses atherosclerosis and improves muscle performance independently of its role in autophagy.
January 31, 2017: Science Signaling
https://www.readbyqxmd.com/read/28143903/tfeb-inhibits-endothelial-cell-inflammation-and-reduces-atherosclerosis
#8
Haocheng Lu, Yanbo Fan, Congzhen Qiao, Wenying Liang, Wenting Hu, Tianqing Zhu, Jifeng Zhang, Y Eugene Chen
Transcription factor EB (TFEB) is a master regulator of autophagy and lysosome biogenesis. We investigated the function of TFEB in vascular biology and pathophysiology and demonstrated that TFEB in endothelial cells inhibited inflammation and reduced atherosclerosis development. Laminar shear stress, which protects against atherosclerosis, increased TFEB abundance in cultured primary human endothelial cells. Furthermore, TFEB overexpression in these cells was anti-inflammatory, whereas TFEB knockdown aggravated inflammation...
January 31, 2017: Science Signaling
https://www.readbyqxmd.com/read/28134625/autophagy-facilitates-macrophage-depots-of-sustained-release-nanoformulated-antiretroviral-drugs
#9
Divya Prakash Gnanadhas, Prasanta K Dash, Brady Sillman, Aditya N Bade, Zhiyi Lin, Diana L Palandri, Nagsen Gautam, Yazen Alnouti, Harris A Gelbard, JoEllyn McMillan, R Lee Mosley, Benson Edagwa, Howard E Gendelman, Santhi Gorantla
Long-acting anti-HIV products can substantively change the standard of care for patients with HIV/AIDS. To this end, hydrophobic antiretroviral drugs (ARVs) were recently developed for parenteral administration at monthly or longer intervals. While shorter-acting hydrophilic drugs can be made into nanocarrier-encased prodrugs, the nanocarrier encasement must be boosted to establish long-acting ARV depots. The mixed-lineage kinase 3 (MLK-3) inhibitor URMC-099 provides this function by affecting autophagy. Here, we have shown that URMC-099 facilitates ARV sequestration and its antiretroviral responses by promoting the nuclear translocation of the transcription factor EB (TFEB)...
January 30, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28122627/therapeutic-potential-of-autophagy-enhancing-agents-in-parkinson-s-disease
#10
REVIEW
Tim E Moors, Jeroen J M Hoozemans, Angela Ingrassia, Tommaso Beccari, Lucilla Parnetti, Marie-Christine Chartier-Harlin, Wilma D J van de Berg
Converging evidence from genetic, pathological and experimental studies have increasingly suggested an important role for autophagy impairment in Parkinson's Disease (PD). Genetic studies have identified mutations in genes encoding for components of the autophagy-lysosomal pathway (ALP), including glucosidase beta acid 1 (GBA1), that are associated with increased risk for developing PD. Observations in PD brain tissue suggest an aberrant regulation of autophagy associated with the aggregation of α-synuclein (α-syn)...
January 25, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28115520/cellular-uptake-and-delivery-of-myeloperoxidase-to-lysosomes-promotes-lipofuscin-degradation-and-lysosomal-stress-in-retinal-cells
#11
Gouri Yogalingam, Amanda R Lee, Donald S Mackenzie, Travis J Maures, Agnes Rafalko, Heather Prill, Geoffrey Berguig, Chuck Hague, Terri Christianson, Sean M Bell, Jonathon H LeBowitz
Neutrophil myeloperoxidase (MPO) catalyzes the H2O2-dependent oxidation of chloride anion to generate hypochlorous acid, a potent antimicrobial agent. Besides its well defined role in innate immunity, aberrant degranulation of neutrophils in several inflammatory diseases leads to redistribution of MPO to the extracellular space, where it can mediate tissue damage by promoting the oxidation of several additional substrates. Here, we demonstrate that mannose-6-phosphate (M6P) receptor-mediated cellular uptake and delivery of MPO to lysosomes of retinal pigmented epithelial (RPE) cells acts to clear this harmful enzyme from the extracellular space, with lysosomal-delivered MPO exhibiting a half-life of 10 hours...
January 23, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28108310/autophagic-dysregulation-in-doxorubicin-cardiomyopathy
#12
REVIEW
Jordan J Bartlett, Purvi C Trivedi, Thomas Pulinilkunnil
Doxorubicin (DOX)-induced cardiotoxicity has been a well-known phenomenon to clinicians and scientists for decades; however, molecular mechanisms underlying DOX cardiotoxicity are still being uncovered. Although the majority of prior research have implicated nuclear and mitochondrial events to be an important etiological aspects of DOX cardiomyopathy, recent discoveries in autophagy have highlighted the renewed interest in the role of lysosome in DOX cardiomyopathy. Indeed, dysregulation of lysosomal autophagy is observed in pre-clinical models of DOX cardiotoxicity...
January 17, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28106924/incidence-clinicopathologic-features-and-fusion-transcript-landscape-of-translocation-renal-cell-carcinomas
#13
Marion Classe, Gabriel G Malouf, Xiaoping Su, Hui Yao, Erika J Thompson, Denaha J Doss, Valérie Grégoire, Julien Lenobin, Jean-Christophe Fantoni, Hélène Sudour-Bonnange, David Khayat, Sébastien Aubert, Nizar M Tannir, Xavier Leroy
AIMS: Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney tumour characterized by translocations involving the transcription factor TFE3 or TFEB. tRCC was introduced into the World Health Organization classification in 2004, but much is still unknown about the natural history, clinicopathologic features, and outcomes of the disease. The aim of this study was to describe the landscape of fusion transcript in a large single-institution series of FISH confirmed tRCCs and then to confront it to morphological and clinical data...
January 20, 2017: Histopathology
https://www.readbyqxmd.com/read/28104689/identification-of-apilimod-as-a-first-in-class-pikfyve-kinase-inhibitor-for-treatment-of-b-cell-non-hodgkin-lymphoma
#14
Sophia Gayle, Sean Landrette, Neil Beeharry, Chris Conrad, Marylens Hernandez, Paul Beckett, Shawn M Ferguson, Talya Mandelkern, Meiling Zheng, Tian Xu, Jonathan Rothberg, Henri Lichenstein
We identified apilimod as an anti-proliferative compound by high-throughput screening of clinical stage drugs. Apilimod exhibits exquisite specificity for PIKfyve lipid kinase and has selective cytotoxic activity in B-cell non-Hodgkin lymphoma (B-NHL) compared to normal cells. Apilimod displays nanomolar activity in vitro, and in vivo studies demonstrate single agent efficacy as well as synergy with approved B-NHL drugs. Using biochemical and knockdown approaches, and discovery of a kinase domain mutation conferring resistance, we demonstrate that apilimod-mediated cytotoxicity is driven by PIKfyve inhibition...
January 19, 2017: Blood
https://www.readbyqxmd.com/read/28102838/autophagy-dysregulation-in-danon-disease
#15
Anna Chiara Nascimbeni, Marina Fanin, Corrado Angelini, Marco Sandri
The autophagy-lysosome system is critical for muscle homeostasis and defects in lysosomal function result in a number of inherited muscle diseases, generally referred to as autophagic vacuolar myopathies (AVMs). Among them, Danon Disease (DD) and glycogen storage disease type II (GSDII) are due to primary lysosomal protein defects. DD is characterized by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. The DD mouse model suggests that inefficient lysosome biogenesis/maturation and impairment of autophagosome-lysosome fusion contribute to the pathogenesis of muscle wasting...
January 19, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28056508/fk506-an-immunosuppressive-drug-induces-autophagy-by-binding-to-the-v-atpase-catalytic-subunit-a-in-neuronal-cells
#16
Dongyoung Kim, Hui-Yun Hwang, Jin Young Kim, Ju Yeon Lee, Jong Shin Yoo, György Marko-Varga, Ho Jeong Kwon
The drug FK506 (tacrolimus, fujimycin) exerts its immunosuppressive effects by regulating the nuclear factor of the activated T-cell (NFAT) family of transcription factors. However, FK506 also exhibits neuroprotective effects, but its direct target proteins that mediate these effects have not been determined. To identify the target proteins responsible for FK506's neuroprotective effects, the drug affinity responsive target stability (DARTS) method was performed using label-free FK506, and LC-MS/MS analysis of the FK506-treated proteome was also performed...
January 6, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28055300/multistep-regulation-of-tfeb-by-mtorc1
#17
Silvia Vega-Rubin-de-Celis, Samuel Peña-Llopis, Meghan Konda, James Brugarolas
The master regulator of lysosome biogenesis, TFEB, is regulated by MTORC1 through phosphorylation at S211, and a S211A mutation increases nuclear localization. However, TFEB(S211A) localizes diffusely in both cytoplasm and nucleus and, as we show, retains regulation by MTORC1. Here, we report that endogenous TFEB is phosphorylated at S122 in an MTORC1-dependent manner, that S122 is phosphorylated in vitro by recombinant MTOR, and that S122 is important for TFEB regulation by MTORC1. Specifically, nuclear localization following MTORC1 inhibition is blocked by a S122D mutation (despite S211 dephosphorylation)...
January 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28017540/transcription-factor-eb-expression-in-early-breast-cancer-relates-to-lysosomal-autophagosomal-markers-and-prognosis
#18
Alexandra Giatromanolaki, Efthimios Sivridis, Dimitra Kalamida, Michael I Koukourakis
BACKGROUND: Disrupting the autophagic balance to trigger autophagic death may open new strategies for cancer therapy. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and may play a role in cancer biology and clinical behavior. METHODS: The expression of TFEB and the lysosomal cancer cell content (expression of lysosomal associated membrane protein 2a [LAMP2a] and cathepsin D) was studied in a series of 100 T1-stage breast carcinomas...
November 23, 2016: Clinical Breast Cancer
https://www.readbyqxmd.com/read/28011087/transcription-factor-eb-controls-metabolic-flexibility-during-exercise
#19
Gelsomina Mansueto, Andrea Armani, Carlo Viscomi, Luca D'Orsi, Rossella De Cegli, Elena V Polishchuk, Costanza Lamperti, Ivano Di Meo, Vanina Romanello, Silvia Marchet, Pradip K Saha, Haihong Zong, Bert Blaauw, Francesca Solagna, Caterina Tezze, Paolo Grumati, Paolo Bonaldo, Jeffrey E Pessin, Massimo Zeviani, Marco Sandri, Andrea Ballabio
The transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis...
January 10, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28009604/renal-cell-carcinoma-with-chromosome-6p-amplification-including-the-tfeb-gene-a-novel-mechanism-of-tumor-pathogenesis
#20
Sean R Williamson, David J Grignon, Liang Cheng, Laura Favazza, Dibson D Gondim, Shannon Carskadon, Nilesh S Gupta, Dhananjay A Chitale, Shanker Kalyana-Sundaram, Nallasivam Palanisamy
Amplification of chromosome 6p has been implicated in aggressive behavior in several cancers, but has not been characterized in renal cell carcinoma (RCC). We identified 9 renal tumors with amplification of chromosome 6p including the TFEB gene, 3 by fluorescence in situ hybridization, and 6 from the Cancer Genome Atlas (TCGA) databases. Patients' ages were 28 to 78 years (median, 61 y). Most tumors were high stage (7/9 pT3a, 2/9 pN1). Using immunohistochemistry, 2/4 were positive for melanocytic markers and cathepsin K...
March 2017: American Journal of Surgical Pathology
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