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https://www.readbyqxmd.com/read/28106924/incidence-clinicopathologic-features-and-fusion-transcript-landscape-of-translocation-renal-cell-carcinomas
#1
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
#2
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
#3
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
#4
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
#5
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 the 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
#6
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
#7
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
#8
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...
December 22, 2016: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28005078/hypericin-mediated-sonodynamic-therapy-induces-autophagy-and-decreases-lipids-in-thp-1-macrophage-by-promoting-ros-dependent-nuclear-translocation-of-tfeb
#9
Xuesong Li, Xin Zhang, Longbin Zheng, Jiayuan Kou, Zhaoyu Zhong, Yueqing Jiang, Wei Wang, Zengxiang Dong, Zhongni Liu, Xiaobo Han, Jing Li, Ye Tian, Yajun Zhao, Liming Yang
Lipid catabolism disorder is the primary cause of atherosclerosis. Transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy to promote lipid degradation. Hypericin-mediated sonodynamic therapy (HY-SDT) has been proved non-invasively inducing THP-1-derived macrophage apoptosis; however, it is unknown whether macrophage autophagy could be triggered by HY-SDT to influence cellular lipid catabolism via regulating TFEB. Here, we report that HY-SDT resulted in the time-dependent THP-1-derived macrophage autophagy activation through AMPK/AKT/mTOR pathway...
December 22, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/28002813/sub-lethal-oxidative-stress-induces-lysosome-biogenesis-via-a-lysosomal-membrane-permeabilization-cathepsin-caspase-3-transcription-factor-eb-dependent-pathway
#10
San Min Leow, Shu Xian Serene Chua, Gireedhar Venkatachalam, Liang Shen, Le Luo, Marie-Veronique Clement
Here we provide evidence to link sub-lethal oxidative stress to lysosomal biogenesis. Exposure of cells to sub-lethal concentrations of exogenously added hydrogen peroxide resulted in cytosol to nuclear translocation of the Transcription Factor EB (TFEB), the master controller of lysosome biogenesis and function. Nuclear translocation of TFEB was dependent upon the activation of a cathepsin-caspase 3 signaling pathway, downstream of a lysosomal membrane permeabilization and accompanied by a significant increase in lysosome numbers as well as induction of TFEB dependent lysosome-associated genes expression such as Ctsl, Lamp2 and its spliced variant Lamp2a, Neu1and Ctsb and Sqstm1 and Atg9b...
December 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27992857/tfeb-ameliorates-the-impairment-of-the-autophagy-lysosome-pathway-in-neurons-induced-by-doxorubicin
#11
Jose Felix Moruno-Manchon, Ndidi-Ese Uzor, Shelli R Kesler, Jeffrey S Wefel, Debra M Townley, Archana Sidalaghatta Nagaraja, Sunila Pradeep, Lingegowda S Mangala, Anil K Sood, Andrey S Tsvetkov
Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets...
December 16, 2016: Aging
https://www.readbyqxmd.com/read/27979841/modeling-alveolar-soft-part-sarcoma-unveils-novel-mechanisms-of-metastasis
#12
Miwa Tanaka, Mizuki Homme, Yukari Yamazaki, Rikuka Shimizu, Yutaka Takazawa, Takuro Nakamura
Alveolar soft part sarcoma (ASPS) is a slowly-growing but highly metastatic sarcoma that affects adolescents and young adults. Its characteristic alveolar structure is constituted by tumor cell nests and an abundant vascular network that is responsible for metastatic activities at the initial stage. Here we have generated a new ex vivo mouse model for ASPS that well recapitulates associated angiogenic and metastatic phenotypes. In mouse ASPS, the tumor cells frequently showed tumor intravasation with the intravascular tumor cells presenting as organoid structures covered with hemangiopericytes, which is also observed in human ASPS...
December 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27977328/transcriptional-regulation-of-core-autophagy-and-lysosomal-genes-by-the-androgen-receptor-promotes-prostate-cancer-progression
#13
Alicia M Blessing, Kimal Rajapakshe, Lakshmi Reddy Bollu, Yan Shi, Mark A White, Alexander H Pham, Chenchu Lin, Philip Jonsson, Constanza J Cortes, Edwin Cheung, Albert R La Spada, Robert C Bast, Fatima A Merchant, Cristian Coarfa, Daniel E Frigo
AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer...
December 15, 2016: Autophagy
https://www.readbyqxmd.com/read/27938510/bile-duct-ligation-induces-atz-globule-clearance-in-a-mouse-model-of-alpha-1-antitrypsin-deficiency
#14
Zahida Khan, Shinichiro Yokota, Yoshihiro Ono, Aaron Bell, Michael Oertel, Donna Stolz, George Michalopoulos
<p>Background: Alpha-1 antitrypsin deficiency (A1ATD) can progress to cirrhosis and hepatocellular carcinoma; however, not all patients are susceptible to severe liver disease. In A1ATD, a toxic gain-of-function mutation generates insoluble ATZ "globules" in hepatocytes, overwhelming protein clearance mechanisms. The relationship between bile acids and hepatocytic autophagy is less clear, but may involve altered gene expression pathways. Based on previous findings that bile duct ligation (BDL) induces autophagy, we hypothesized that retained bile acids may have hepatoprotective effects in PiZZ transgenic mice, which model A1ATD...
18, 2016: Gene Expression
https://www.readbyqxmd.com/read/27892768/tfeb-and-tfe3-the-art-of-multi-tasking-under-stress-conditions
#15
José A Martina, Rosa Puertollano
Cellular adaptation response to a myriad of stressors is key for survival. The lysosomal/autophagy pathway is inextricably connected to the stress response regulation. Two transcription factors, TFEB and TFE3, have recently emerged as master regulators of this degradative pathway. Their function modulating different cellular pathways will be discussed.
November 28, 2016: Transcription
https://www.readbyqxmd.com/read/27892481/autophagy-is-required-for-pdac-glutamine-metabolism
#16
Ju-Won Seo, Jungwon Choi, So-Yeon Lee, Suhyun Sung, Hyun Ju Yoo, Min-Ji Kang, Heesun Cheong, Jaekyoung Son
Macroautophagy (autophagy) is believed to maintain energy homeostasis by degrading unnecessary cellular components and molecules. Its implication in regulating cancer metabolism recently started to be uncovered. However, the precise roles of autophagy in cancer metabolism are still unclear. Here, we show that autophagy plays a critical role in glutamine metabolism, which is required for tumor survival. Pancreatic ductal adenocarcinoma (PDAC) cells require both autophagy and typical glutamine transporters to maintain intracellular glutamine levels...
November 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27884963/ectopic-fat-deposition-contributes-to-age-associated-pathology-in-caenorhabditis-elegans
#17
Konstantinos Palikaras, Meropi Mari, Barbara Petanidou, Angela Pasparaki, George Filippidis, Nektarios Tavernarakis
Age-dependent collapse of lipid homeostasis results in spillover of lipids and excessive fat deposition in nonadipose tissues. Ectopic fat contributes to lipotoxicity and has been implicated in the development of a metabolic syndrome that increases risk of age-associated diseases. However, the molecular mechanisms coupling ectopic fat accumulation with aging remain obscure. Here, we use nonlinear imaging modalities to visualize and quantify age-dependent ectopic lipid accumulation in Caenorhabditis elegans We find that aging is accompanied by pronounced deposition of lipids in nonadipose tissues, including the nervous system...
January 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/27875531/loss-of-c9orf72-enhances-autophagic-activity-via-deregulated-mtor-and-tfeb-signaling
#18
Janet Ugolino, Yon Ju Ji, Karen Conchina, Justin Chu, Raja Sekhar Nirujogi, Akhilesh Pandey, Nathan R Brady, Anne Hamacher-Brady, Jiou Wang
The most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia is a hexanucleotide repeat expansion in C9orf72. Here we report a study of the C9orf72 protein by examining the consequences of loss of C9orf72 functions. Deletion of one or both alleles of the C9orf72 gene in mice causes age-dependent lethality phenotypes. We demonstrate that C9orf72 regulates nutrient sensing as the loss of C9orf72 decreases phosphorylation of the mTOR substrate S6K1. The transcription factor EB (TFEB), a master regulator of lysosomal and autophagy genes, which is negatively regulated by mTOR, is substantially up-regulated in C9orf72 loss-of-function animal and cellular models...
November 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27875098/hlh-30-tfeb-mediated-autophagy-functions-in-a-cell-autonomous-manner-for-epithelium-intrinsic-cellular-defense-against-bacterial-pore-forming-toxin-in-c-elegans
#19
Huan-Da Chen, Cheng-Yuan Kao, Bang-Yu Liu, Shin-Whei Huang, Cheng-Ju Kuo, Jhen-Wei Ruan, Yen-Hung Lin, Cheng-Rung Huang, Yu-Hung Chen, Horng-Dar Wang, Raffi V Aroian, Chang-Shi Chen
Autophagy is an evolutionarily conserved intracellular system that maintains cellular homeostasis by degrading and recycling damaged cellular components. The transcription factor HLH-30/TFEB-mediated autophagy has been reported to regulate tolerance to bacterial infection, but less is known about the bona fide bacterial effector that activates HLH-30 and autophagy. Here, we reveal that bacterial membrane pore-forming toxin (PFT) induces autophagy in an HLH-30-dependent manner in Caenorhabditis elegans. Moreover, autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and repair of membrane-pore cell-autonomously in the PFT-targeted intestinal cells in C...
November 22, 2016: Autophagy
https://www.readbyqxmd.com/read/27864122/sclerosing-tfeb-rearrangement-renal-cell-carcinoma-a-recurring-histologic-pattern
#20
Sean R Williamson, John N Eble, Nallasivam Palanisamy
Renal cell carcinoma with TFEB rearrangement [t(6;11)(p21;q13)] was initially recognized to be composed of dual populations of large cells with clear cytoplasm and small cells forming rosettes around hyaline material. With increasing awareness, however, the spectrum of described morphology has been found to be more heterogeneous. We report a 54 year-old woman who underwent partial nephrectomy for a 2.4 cm renal mass, composed of fibrosis, hyalinization, calcification and ossification, and a smaller component of epithelioid cells...
November 15, 2016: Human Pathology
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