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Edgard M Mejia, Hana Zegallai, Eric D Bouchard, Versha Banerji, Amir Ravandi, Grant M Hatch
The mitochondrial polyglycerophospholipid cardiolipin (CL) is remodeled to obtain specific fatty acyl chains. This is predominantly accomplished by the transacylase enzyme tafazzin (TAZ). Barth Syndrome (BTHS) patients with TAZ gene mutations exhibit impaired TAZ activity and loss in mitochondrial respiratory function. Previous studies identified monolysocardiolipin acyltransferase-1 (MLCL AT-1) as a mitochondrial enzyme capable of remodelling CL with fatty acid. In this study, we analyzed what relationship, if any, exits between TAZ and MLCL AT-1 with regard to CL remodeling and if transfection of BTHS lymphoblasts with a MLCL AT-1 expression construct improves mitochondrial respiratory function...
March 21, 2018: Journal of Biological Chemistry
Jennifer F Knight, Vanessa Y C Sung, Elena Kuzmin, Amber L Couzens, Danielle A de Verteuil, Colin D H Ratcliffe, Paula P Coelho, Radia M Johnson, Payman Samavarchi-Tehrani, Tina Gruosso, Harvey W Smith, Wontae Lee, Sadiq M Saleh, Dongmei Zuo, Hong Zhao, Marie-Christine Guiot, Ryan R Davis, Jeffrey P Gregg, Christopher Moraes, Anne-Claude Gingras, Morag Park
Triple-negative breast cancers (TNBCs) display a complex spectrum of mutations and chromosomal aberrations. Chromosome 5q (5q) loss is detected in up to 70% of TNBCs, but little is known regarding the genetic drivers associated with this event. Here, we show somatic deletion of a region syntenic with human 5q33.2-35.3 in a mouse model of TNBC. Mechanistically, we identify KIBRA as a major factor contributing to the effects of 5q loss on tumor growth and metastatic progression. Re-expression of KIBRA impairs metastasis in vivo and inhibits tumorsphere formation by TNBC cells in vitro...
March 20, 2018: Cell Reports
Jeffrey K Holden, Christian N Cunningham
The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer...
March 20, 2018: Cancers
Tomohiro Kimura, Atsuko Kimura, Mindong Ren, Bob Berno, Yang Xu, Michael Schlame, Richard M Epand
Tafazzin is the mitochondrial enzyme that catalyzes transacylation between a phospholipid and a lysophospholipid in remodeling. Mutations in tafazzin cause Barth syndrome, a potentially life-threatening disease with the major symptom of cardiomyopathy. In the tafazzin-deficient heart, cardiolipin (CL) acyl chains become abnormally heterogeneous unlike those in the normal heart with a single dominant linoleoyl species; tetralinoleoyl CL. In addition, the amount of CL decreases and monolysocardiolipin (MLCL) accumulates...
March 20, 2018: Biochemistry
Yulei Zhao, Tess Montminy, Taha Azad, Elizabeth Lightbody, Yawei Hao, Sandip SenGupta, Eric Asselin, Christopher Jb Nicol, Xiaolong Yang
Breast cancer (BC) is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB occur in many BC cases. In recent years, activation of the Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have been found to be important for BC development and progression. However, there is no evidence that PI3K interacts with YAP/TAZ in mammary tumorigenesis. Using a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, PIK3CB was identified as a transformation inducing kinase...
March 15, 2018: Molecular Cancer Research: MCR
Saber Ben Mimoun, Alain Mauviel
The ubiquitous distribution of both Hippo and TGF-ß signaling cascade components and their critical implication in tissue homeostasis and disease has led to the discovery of a remarkable slew of interesting and unique features regarding their functional crosstalks. Upstream cellular cues regulating the Hippo pathway, including cell-cell contacts and apico-basal cell polarity have been well characterized. Herein, we provide an overview of the published models of compartmentalized signaling crosstalk mechanisms between Hippo signaling and the TGF-ß/SMAD pathway...
March 12, 2018: International Journal of Biochemistry & Cell Biology
Sang Yeon Cho, Jang Wook Gwak, Yoo Chul Shin, Daeju Moon, Jihyuok Ahn, Hyon Woo Sol, Sungha Kim, Gwanghun Kim, Hyun Mu Shin, Kyung Ha Lee, Ji Yeon Kim, Jin Soo Kim
Yes-associated protein 1 (YAP1) is a transcriptional regulator of the Hippo pathway, which regulates the development and progression of a number of types of cancer, including that of the colon. In the present study, the expression levels of Hippo pathway genes and their clinical significance were investigated in 458 patients with colon adenocarcinoma (COAD), the most frequently diagnosed neoplastic disease globally, using data obtained from The Cancer Genome Atlas database. Notably, mRNA expression of YAP1 was higher in COAD than in other types of gastrointestinal tract cancer...
April 2018: Oncology Letters
T Azad, H J Janse van Rensburg, E D Lightbody, B Neveu, A Champagne, A Ghaffari, V R Kay, Y Hao, H Shen, B Yeung, B A Croy, K L Guan, F Pouliot, J Zhang, C J B Nicol, X Yang
The Hippo pathway is a central regulator of tissue development and homeostasis, and has been reported to have a role during vascular development. Here we develop a bioluminescence-based biosensor that monitors the activity of the Hippo core component LATS kinase. Using this biosensor and a library of small molecule kinase inhibitors, we perform a screen for kinases modulating LATS activity and identify VEGFR as an upstream regulator of the Hippo pathway. We find that VEGFR activation by VEGF triggers PI3K/MAPK signaling, which subsequently inhibits LATS and activates the Hippo effectors YAP and TAZ...
March 13, 2018: Nature Communications
Benjamin Yeung, Prem Khanal, Virja Mehta, Laura Trinkle-Mulcahy, Xiaolong Yang
The Hippo pathway is a signalling cascade that plays important roles in organ size control, tumorigenesis, metastasis, stress response, stem cell differentiation and renewal during development and tissue homeostasis, and mechanotransduction. Recently, we and others have shown that loss of the Hippo pathway core component LATS or overexpression of its downstream targets YAP and its paralog TAZ causes resistance of cancer cells to anti-tubulin drugs. However, YAP and TAZ mediates anti-tubulin drug-induced apoptosis independent of its upstream regulator LATS and the Hippo pathway...
March 9, 2018: Molecular Cancer Research: MCR
Alice Giuliodori, Giorgia Beffagna, Giulia Marchetto, Chiara Fornetto, Francesco Vanzi, Stefano Toppo, Nicola Facchinello, Mattia Santimaria, Andrea Vettori, Stefania Rizzo, Mila Della Barbera, Kalliopi Pilichou, Francesco Argenton, Gaetano Thiene, Natascia Tiso, Cristina Basso
Aims: Arrhythmogenic cardiomyopathy (AC) is an inherited heart disease characterized by life-threatening ventricular arrhythmias and fibro-fatty replacement of the myocardium. More than 60% of AC patients show pathogenic mutations in genes encoding for desmosomal proteins. By focusing our attention on the AC8 form, linked to the junctional protein Desmoplakin (DSP), we present here a zebrafish model of DSP deficiency, exploited to identify early changes of cell signalling in the cardiac region...
March 7, 2018: Cardiovascular Research
Michael D Deel, Katherine K Slemmons, Ashley R Hinson, Katia C Genadry, Breanne A Burgess, Lisa E S Crose, Nina Kuprasertkul, Kristianne M Oristian, Rex C Bentley, Corinne M Linardic
PURPOSE: Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature PAX3-FOXO1 (P3F) fusion gene. 5-year survival for aRMS is <50%, with no improvement in over four decades. Although the transcriptional co-activator TAZ is oncogenic in carcinomas, the role of TAZ in sarcomas is poorly understood. The aim of this study was to investigate the role of TAZ in P3F-aRMS tumorigenesis. EXPERIMENTAL DESIGN: After determining from public datasets that TAZ is upregulated in human aRMS transcriptomes, we evaluated whether TAZ is also upregulated in our myoblast-based model of P3F-initiated tumorigenesis, and performed IHC staining of 63 human aRMS samples from tissue microarrays...
March 7, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yumin Zhu, Yaping Wu, Jie Cheng, Qiong Wang, Zhongwu Li, Yanling Wang, Dongmiao Wang, Hua Wang, Weibing Zhang, Jinhai Ye, Hongbing Jiang, Lin Wang
BACKGROUND: Adipose-derived stem cells (ADSCs) are an attractive cell source for bone tissue engineering and have great potential for bone regeneration and defect repair. The transcriptional coactivator with PDZ-binding motif (TAZ) has been demonstrated to modulate osteogenic and adipogenic differentiation of mesenchymal stem cells. However, its roles during ADSC differentiation and therapeutic potentials for bone regeneration have as yet not been well established. METHODS: TAZ expression was measured during osteogenic differentiation of ADSCs in vitro...
March 7, 2018: Stem Cell Research & Therapy
Kevin M Tharp, Michael S Kang, Greg A Timblin, Jon Dempersmier, Garret E Dempsey, Peter-James H Zushin, Jaime Benavides, Catherine Choi, Catherine X Li, Amit K Jha, Shingo Kajimura, Kevin E Healy, Hei Sook Sul, Kaoru Saijo, Sanjay Kumar, Andreas Stahl
The activation of brown/beige adipose tissue (BAT) metabolism and the induction of uncoupling protein 1 (UCP1) expression are essential for BAT-based strategies to improve metabolic homeostasis. Here, we demonstrate that BAT utilizes actomyosin machinery to generate tensional responses following adrenergic stimulation, similar to muscle tissues. The activation of actomyosin mechanics is critical for the acute induction of oxidative metabolism and uncoupled respiration in UCP1+ adipocytes. Moreover, we show that actomyosin-mediated elasticity regulates the thermogenic capacity of adipocytes via the mechanosensitive transcriptional co-activators YAP and TAZ, which are indispensable for normal BAT function...
March 6, 2018: Cell Metabolism
Hiroki Goto, Miki Nishio, Yoko To, Tatsuya Oishi, Yosuke Miyachi, Tomohiko Maehama, Hiroshi Nishina, Haruhiko Akiyama, Tak Wah Mak, Yuma Makii, Taku Saito, Akihiro Yasoda, Noriyuki Tsumaki, Akira Suzuki
Hippo signaling is modulated in response to cell density, external mechanical forces, or rigidity of the extracellular matrix (ECM). The Mps one binder kinase activator (MOB) adaptor proteins are core components of Hippo signaling and have important effects on Yes-associated protein-1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), which are potent transcriptional regulators. YAP1/TAZ are key contributors to cartilage and bone development but the molecular mechanisms by which the Hippo pathway controls chondrogenesis are largely unknown...
March 6, 2018: Development
Presha Rajbhandari, Gonzalo Lopez, Claudia Capdevila, Beatrice Salvatori, Jiyang Yu, Ruth Rodriguez-Barrueco, Daniel Martinez, Mark Yarmarkovich, Nina Weichert-Leahey, Brian J Abraham, Mariano J Alvarez, Archana Iyer, Jo Lynne Harenza, Derek Oldridge, Katleen De Preter, Jan Koster, Shahab Asgharzadeh, Robert C Seeger, Jun S Wei, Javed Khan, Jo Vandesompele, Pieter Mestdagh, Rogier Versteeg, A Thomas Look, Richard A Young, Antonio Iavarone, Anna Lasorella, Jose M Silva, John M Maris, Andrea Califano
High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator (MR) proteins that were conserved across independent cohorts...
March 6, 2018: Cancer Discovery
Jiehong Guo, William A Stubbings, Kevin Romanak, Linh V Nguyen, Liisa Jantunen, Lisa Melymuk, Victoria Arrandale, Miriam L Diamond, Marta Venier
A high molecular weight compound, 2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5-triazine (TTBP-TAZ), was detected during the analysis of brominated flame retardants in dust samples collected from an electrical and electronic waste (e-waste) recycling facility in Ontario, Canada. Gas chromatography coupled with both high-resolution and low-resolution mass spectrometry (MS) was used to determine TTBP-TAZ's chemical structure and concentrations. To date, TTBP-TAZ has only been detected in plastic casings of electrical and electronic equipment and house dust from The Netherlands...
March 6, 2018: Environmental Science & Technology
Hubert Rehrauer, Licun Wu, Walter Blum, Lazslo Pecze, Thomas Henzi, Véronique Serre-Beinier, Catherine Aquino, Bart Vrugt, Marc de Perrot, Beat Schwaller, Emanuela Felley-Bosco
Chronic exposure to intraperitoneal asbestos triggered a marked response in the mesothelium well before tumor development. Macrophages, mesothelial precursor cells, cytokines, and growth factors accumulated in the peritoneal lavage. Transcriptome profiling revealed YAP/TAZ activation in inflamed mesothelium with further activation in tumors, paralleled by increased levels of cells with nuclear YAP/TAZ. Arg1 was one of the highest upregulated genes in inflamed tissue and tumor. Inflamed tissue showed increased levels of single-nucleotide variations, with an RNA-editing signature, which were even higher in the tumor samples...
March 6, 2018: Oncogene
Natalia D Popowicz, Sean J O'Halloran, Deirdre Fitzgerald, Y C Gary Lee, David A Joyce
Piperacillin, in combination with tazobactam is a common first-line antibiotic used for the treatment of pleural infection, however its pleural pharmacokinetics and penetration has not previously been reported. The objective of this work was to develop and validate a rapid and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay for quantification of piperacillin (PIP) and tazobactam (TAZ). PIP and TAZ were extracted from both human plasma and pleural fluid samples by protein precipitation in methanol containing the internal standards (IS) piperacillin-d5 (PIP-d5 ) and sulbactam (SUL)...
February 24, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Ting Zhan, Xiaodong Huang, Xia Tian, Xiaoli Chen, Yu Ding, Hesheng Luo, Yadong Zhang
Drug resistance is a major cause of treatment failure in pancreatic cancer. The limited evidence indicates the involvement of miR-455-3p in chemotherapy resistance of cancer. Here we observed by qPCR that miR-455-3p was significantly decreased in pancreatic cancer tissues and cell lines. We then confirmed that the inhibition of miR-455-3p increased cell proliferation and gemcitabine resistance of pancreatic cancer, whereas forced overexpression of miR-455-3p had the opposite effect. Furthermore, we demonstrated that TAZ, which is associated with drug resistance of pancreatic cancer, is a new direct downstream target of miR-455-3p...
March 2, 2018: Molecular Therapy. Nucleic Acids
Ling Guo, Ting Cai, Keng Chen, Rong Wang, Jiaxin Wang, Chunhong Cui, Jifan Yuan, Kuo Zhang, Zhongzhen Liu, Yi Deng, Guozhi Xiao, Chuanyue Wu
Precise control of mesenchymal stem cell (MSC) differentiation is critical for tissue development and regeneration. We show here that kindlin-2 is a key determinant of MSC fate decision. Depletion of kindlin-2 in MSCs is sufficient to induce adipogenesis and inhibit osteogenesis in vitro and in vivo. Mechanistically, kindlin-2 regulates MSC differentiation through controlling YAP1/TAZ at both the transcript and protein levels. Kindlin-2 physically associates with myosin light-chain kinase in response to mechanical cues of cell microenvironment and intracellular signaling events and promotes myosin light-chain phosphorylation...
March 1, 2018: Journal of Cell Biology
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