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S Pontikakis, C Papadaki, M Tzardi, M Trypaki, M Sfakianaki, F Koinis, E Lagoudaki, L Giannikaki, A Kalykaki, E Kontopodis, Z Saridaki, N Malamos, V Georgoulias, J Souglakos
To evaluate the predictive value of genes involved in resistance to platinum-taxane chemotherapy in patients with epithelial ovarian cancer (EOC). Microdissected formalin-fixed tumoral samples from 187 EOC patients' primary tumors (90 and 97 samples from matched patients in the experimental and validation sets, respectively) were analyzed. All specimens were analyzed for ATP7b, BRCA1, BRCA2, PARP1, UIMC1(RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) mRNA expression by quantitative real-time PCR...
October 25, 2016: Pharmacogenomics Journal
Jessica E Maxwell, Scott K Sherman, James R Howe
Pancreatic neuroendocrine tumors (PNET) are rare tumors, but have been increasing in incidence. Although typically thought of as indolent, more than half of patients present with metastatic disease. For many years, the only mutations commonly known in these tumors were those in the MEN1 gene. Recently, the genetics underlying PNETs have been further defined through exome sequencing. The most frequent alterations found in sporadic PNETs are in MEN1, DAXX/ATRX, and a variety of genes in the mTOR pathway. Confirmation of these mutations has prompted trials with a number of drugs active in these pathways, and two drugs were eventually approved in 2011-sunitinib and everolimus...
October 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sivan Subburaju, Andrew J Coleman, Miles G Cunningham, W Brad Ruzicka, Francine M Benes
GABAergic dysfunction in hippocampus, a key feature of schizophrenia (SZ), may contribute to cognitive impairment in this disorder. In stratum oriens (SO) of sector CA3/2 of the human hippocampus, a network of genes involved in the regulation of glutamic acid decarboxylase GAD67 has been identified. Several of the genes in this network including epigenetic factors histone deacetylase 1 (HDAC1) and death-associated protein 6 (DAXX), the GABAergic enzyme GAD65 as well as the kainate receptor (KAR) subunits GluR6 and 7 show significant changes in expression in this area in SZ...
October 12, 2016: Cerebral Cortex
Almira Nasirden, Tsuyoshi Saito, Yuki Fukumura, Kieko Hara, Keisuke Akaike, Aiko Kurisaki-Arakawa, Miki Asahina, Atsushi Yamashita, Ran Tomomasa, Takuo Hayashi, Atsushi Arakawa, Takashi Yao
The prognostic value of BRAF (V600E) and TERT promoter mutation in papillary thyroid carcinoma (PTC) is controversial. We examined alterations in BRAF (V600E) and TERT promoter by PCR-direct sequencing in PTC of 144 Japanese patients. Alternative lengthening of telomeres was examined as another mechanism of telomere maintenance by immunohistochemical staining for ATRX and DAXX. Of the clinicopathological characteristics, regional lymph node metastasis, extra-thyroid extension, multifocality/intrathyroidal spread, and advanced stage (III/V) were associated with shorter disease-free survival rate (DFSR)...
October 7, 2016: Virchows Archiv: An International Journal of Pathology
Shaowei Sun, Juan Wen, Fei Qiu, Yufang Yin, Guina Xu, Tianping Li, Juan Nie, Guozuo Xiong, Caiping Zhang, Duangfang Liao, Jianxiong Chen, Qinhui Tuo
Daxx is a highly conserved nuclear transcriptional factor, which has been implicated in many nuclear processes including transcription and cell cycle regulation. Our previous study demonstrated Daxx also plays a role in regulation of intracellular cholesterol content. Daxx contains several domains that are essential for interaction with a growing number of proteins. To delineate the underlying mechanism of hypocholesterolemic activity of Daxx, we constructed a set of plasmids which can be used to overexpress different fragments of Daxx and transfected to HepG2 cells...
September 23, 2016: Biochemical and Biophysical Research Communications
Joo Young Kim, Jacqueline A Brosnan-Cashman, Soyeon An, Sung Joo Kim, Ki Byung Song, Min-Sun Kim, Mi-Ju Kim, Dae Wook Hwang, Alan K Meeker, Eunsil Yu, Song Cheol Kim, Ralph H Hruban, Christopher M Heaphy, Seung-Mo Hong
PURPOSE: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNETs). EXPERIMENTAL DESIGN: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors. RESULTS: In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20...
September 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Donglai Wang, Ning Kon, Gorka Lasso, Le Jiang, Wenchuan Leng, Wei-Guo Zhu, Jun Qin, Barry Honig, Wei Gu
Although lysine acetylation is now recognized as a general protein modification for both histones and non-histone proteins, the mechanisms of acetylation-mediated actions are not completely understood. Acetylation of the C-terminal domain (CTD) of p53 (also known as TP53) was an early example of non-histone protein acetylation and its precise role remains unclear. Lysine acetylation often creates binding sites for bromodomain-containing 'reader' proteins. Here we use a proteomic screen to identify the oncoprotein SET as a major cellular factor whose binding with p53 is dependent on CTD acetylation status...
September 14, 2016: Nature
Theresa Kreilmeier, Sandra Sampl, Abigail J Deloria, Ingrid Walter, Martin Reifinger, Marlene Hauck, Luke B Borst, Klaus Holzmann, Miriam Kleiter
Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism (TMM) found in some human tumors such as sarcomas. Canine tumors are not characterized for ALT and the study aim was to identify if the ALT phenotype exists in canine sarcomas. Sixty-four canine sarcoma samples (20 snap-frozen, 44 FFPE) as well as six canine sarcoma cell lines were screened for ALT by C-circle assay. ALT was further evaluated by measuring telomere length via qPCR and telomere restriction-fragments including pulsed-field electrophoresis...
September 1, 2016: Molecular Carcinogenesis
Hongda Huang, Zhong Deng, Olga Vladimirova, Andreas Wiedmer, Fang Lu, Paul M Lieberman, Dinshaw J Patel
The histone H3.3 chaperone DAXX is implicated in formation of heterochromatin and transcription silencing, especially for newly infecting DNA virus genomes entering the nucleus. Epstein-Barr virus (EBV) can efficiently establish stable latent infection as a chromatinized episome in the nucleus of infected cells. The EBV tegument BNRF1 is a DAXX-interacting protein required for the establishment of selective viral gene expression during latency. Here we report the structure of BNRF1 DAXX-interaction domain (DID) in complex with DAXX histone-binding domain (HBD) and histones H3...
2016: Nature Communications
Friederike Neumann, Manja Czech-Sioli, Claudia Schmidt, Thomas Dobner, Adam Grundhoff, Sabrina Schreiner, Nicole Fischer
Merkel cell polyomavirus (MCPyV) is associated with Merkel cell carcinoma (MCC), a rare but aggressive skin cancer. The virus is highly prevalent: 60-80% of adults are seropositive; however, cells permissive for MCPyV infection are unknown. Consequently, very little information about the MCPyV life cycle is available. Until recently, MCPyV replication could only be studied using a semi permissive in vitro replication system, which we and others previously published. MCPyV replication most likely depends on subnuclear structures such as PML nuclear bodies, which are known to play regulatory roles in the infection of many DNA viruses...
August 30, 2016: Journal of General Virology
Yang Hu, Guang Shi, Laichen Zhang, Feng Li, Yuanling Jiang, Shuai Jiang, Wenbin Ma, Yong Zhao, Zhou Songyang, Junjiu Huang
Activation of telomerase or alternative lengthening of telomeres (ALT) is necessary for tumours to escape from dysfunctional telomere-mediated senescence. Anti-telomerase drugs might be effective in suppressing tumour growth in approximately 85-90% of telomerase-positive cancer cells. However, there are still chances for these cells to bypass drug treatment after switching to the ALT mechanism to maintain their telomere integrity. But the mechanism underlying this switch is unknown. In this study, we used telomerase-positive cancer cells (HTC75) to discover the mechanism of the telomerase-ALT switch by inducing telomere-specific DNA damage, alpha-thalassemia X-linked syndrome protein (ATRX) knockdown and deletion of death associated protein (DAXX)...
2016: Scientific Reports
Rui-Ting Chen, Peng Jiao, Yan Lu, Hu-Hu Xin, Deng-Pan Zhang, Mei-Xian Wang, Shuang Liang, Yun-Gen Miao
The apoptosis mechanisms in mammals were investigated relatively clearly. However, little is known about how apoptosis is achieved at a molecular level in silkworm cells. We cloned a caspase homologous gene named BmDredd (where Bm is Bombyx mori and Dredd is death-related ced-3/Nedd2-like caspase) in BmN cells from the ovary of Bm and analyzed its biological information. We constructed the N-terminal, C-terminal, and overexpression vector of BmDredd, respectively. Our results showed that the transcriptional expression level of BmDredd was increased in the apoptotic BmN cells...
November 2016: Archives of Insect Biochemistry and Physiology
Ismini Lasithiotaki, Eliza Tsitoura, Anastasios Koutsopoulos, Eleni Lagoudaki, Chara Koutoulaki, George Pitsidianakis, Demetrios A Spandidos, Nikolaos M Siafakas, George Sourvinos, Katerina M Antoniou
Merkel Cell Polyoma Virus (MCPyV) infection has been associated with non-small cell lung cancer (NSCLC). Viruses can manipulate cellular miRNAs or have a profound impact on cellular miRNA expression to control host regulatory pathways. In this study, we evaluated the expression profiles of cancer-associated and virally affected host microRNAs miR-21, miR-145, miR-146a, miR-155, miR-302c, miR-367 and miR-376c in a series of NSCLC tissue samples as well as in samples from "healthy" sites, distant from the tumour region that were either positive or negative for MCPyV DNA...
August 11, 2016: Oncotarget
Stefan Donath, Junfeng An, Sabrina Lin Lin Lee, Karen Gertz, Anna Lena Datwyler, Ulrike Harms, Susanne Müller, Tracy Deanne Farr, Martina Füchtemeier, Gisela Lättig-Tünnemann, Janet Lips, Marco Foddis, Larissa Mosch, René Bernard, Ulrike Grittner, Mustafa Balkaya, Golo Kronenberg, Ulrich Dirnagl, Matthias Endres, Christoph Harms
UNLABELLED: The aim of this study was to explore the signaling and neuroprotective effect of transactivator of transcription (TAT) protein transduction of the apoptosis repressor with CARD (ARC) in in vitro and in vivo models of cerebral ischemia in mice. In mice, transient focal cerebral ischemia reduced endogenous ARC protein in neurons in the ischemic striatum at early reperfusion time points, and in primary neuronal cultures, RNA interference resulted in greater neuronal susceptibility to oxygen glucose deprivation (OGD)...
August 3, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Mélissa Lessard-Beaudoin, Mélissa Laroche, Marie-Josée Demers, Catherine Duclos, Jean-Bernard Denault, Guillaume Grenier, Sean-Patrick Riechers, Erich E Wanker, Rona K Graham
Death-associated protein 6 (DAXX) is a ubiquitous protein implicated in various cellular processes such as apoptosis, tumorigenesis, development and transcription. The role of DAXX is however ambiguous and many contradictory results regarding its function in apoptosis upon various cellular stresses are described in the literature. In order to have a better understanding of the role of DAXX throughout the entire organism under physiological stress conditions, we have characterized the mRNA levels, protein expression and the proteolytic processing of DAXX in the normal aging process in peripheral organs and brain regions in C57BL/6 male mice...
November 2016: Biogerontology
Anja M Schmitt, Ilaria Marinoni, Annika Blank, Aurel Perren
The recent findings on the roles of death-associated protein 6/α-thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a cross-species study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs...
September 2016: Endocrine Pathology
Aatur D Singhi, Ta-Chiang Liu, Justin L Roncaioli, Dengfeng Cao, Herbert J Zeh, Amer H Zureikat, Allan Tsung, J Wallis Marsh, Kenneth K Lee, Melissa E Hogg, Nathan Bahary, Randall Brand, Kevin M McGrath, Adam Slivka, Kristi L Cressman, Kimberly Fuhrer, Roderick J O'Sullivan
PURPOSE: Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole exome sequencing has identified recurrent mutations in the genes DAXX and ATRX, which correlate with loss of protein expression and alternative lengthening of telomeres (ALT). Both ALT and DAXX/ATRX loss were initially reported to be associated with a favorable prognosis; however, recent studies suggest the contrary. Our aims were to assess the prevalence and prognostic significance of ALT and DAXX/ATRX in both primary and metastatic PanNETs...
July 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Maria de Leon, Horacio Cardenas, Edyta Vieth, Robert Emerson, Matthew Segar, Yunlong Liu, Kenneth Nephew, Daniela Matei
OBJECTIVES: Epigenetic alterations have been implicated in the development of platinum resistance in ovarian cancer (OC). In this study, we aimed to identify DNA methylation changes in platinum resistant tumors and their functional implications. METHODS: To identify DNA methylation alterations we used the Illumina 450k DNA methylation array and profiled platinum sensitive and resistant OC xenografts. Validation analyses employed RT-PCR and immunohistochemistry (IHC)...
September 2016: Gynecologic Oncology
Alexander S Hahn, Anna K Großkopf, Doris Jungnickl, Brigitte Scholz, Armin Ensser
UNLABELLED: Nuclear domain 10 (ND10) components restrict herpesviral infection, and herpesviruses antagonize this restriction by a variety of strategies, including degradation or relocalization of ND10 proteins. The rhesus monkey rhadinovirus (RRV) shares many key biological features with the closely related Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) and readily infects cells of both human and rhesus monkey origin. We used the clustered regularly interspaced short palindromic repeat-Cas9 (CRISPR-Cas9) technique to generate knockout (ko) cells for each of the four ND10 components, PML, SP100, DAXX, and ATRX...
September 1, 2016: Journal of Virology
Wenzel M Hackeng, Lodewijk A A Brosens, Katherine E Poruk, Michaël Noë, Waki Hosoda, Justin S Poling, Anthony Rizzo, Martha Campbell-Thompson, Mark A Atkinson, Björn Konukiewitz, Günter Klöppel, Christopher M Heaphy, Alan K Meeker, Laura D Wood
Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in situ hybridization (FISH) to a series of well-characterized sporadic neuroendocrine microadenomas and investigated the prevalence of alterations in known PanNET driver genes (MEN1 and ATRX/DAXX) in these same tumors using immunohistochemistry for the encoded proteins...
October 2016: Human Pathology
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