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Ross S Firestone, Scott A Cameron, Peter C Tyler, Rodrigo Gay Ducati, Adam Z Spitz, Vern L Schramm
5'-Methylthioadenosine phosphorylase (MTAP) and 5'-methylthioadenosine nucleosidase (MTAN) catalyze the phosphorolysis and hydrolysis of 5'-methylthioadenosine (MTA), respectively. Both enzymes have low KM values for their substrates. Kinetic assays for these enzymes are challenging, as the ultraviolet absorbance spectra for reactant MTA and product adenine are similar. We report a new assay using 2-amino-5'-methylthioadenosine (2AMTA) as an alternative substrate for MTAP and MTAN enzymes. Hydrolysis or phosphorolysis of 2AMTA forms 2,6-diaminopurine, a fluorescent and easily quantitated product...
October 25, 2016: Analytical Chemistry
Joaquim Carreras, Yara Yukie Kikuti, Sílvia Beà, Masashi Miyaoka, Shinichiro Hiraiwa, Haruka Ikoma, Ryoko Nagao, David Martin-Garcia, Itziar Salaverria, Ai Sato, Ichiki Akifumi, Giovanna Roncador, Juan F Garcia, Kiyoshi Ando, Elias Campo, Naoya Nakamura
AIMS AND METHODS: We aimed to define the clinicopathological characteristics of 29 primary sinonasal diffuse large B-cell lymphoma (DLBCL(sn) ) in a series of 240 DLBCL(all ()(NOS)()) including DLBCL(sn) training set (n=11) and validation set (n=18), and DLBCL(non-sn) (n=211). RESULTS: In the training set 82% had non-GCB phenotype and 18% were EBER(+) . The genomic profile showed gains((+)) of 1q21.3q31.2 (55%), 10q24.1 (46%), 11q14.1 (46%) and 18q12.1q23 (46%); losses((-)) of 6q26q27 (55%) and 9p21...
October 24, 2016: Histopathology
A Sangalli, G Malerba, G Tessari, M Rodolfo, M Gomez-Lira
No abstract text is available yet for this article.
October 20, 2016: Experimental Dermatology
Frederik C Henrich, Katrin Singer, Kerstin Poller, Luise Bernhardt, Carolin D Strobl, Katharina Limm, Axel P Ritter, Eva Gottfried, Simon Völkl, Benedikt Jacobs, Katrin Peter, Dimitrios Mougiakakos, Katja Dettmer, Peter J Oefner, Anja-Katrin Bosserhoff, Marina P Kreutz, Michael Aigner, Andreas Mackensen
The immunosuppressive tumor microenvironment represents one of the main obstacles for immunotherapy of cancer. The tumor milieu is among others shaped by tumor metabolites such as 5'-deoxy-5'-methylthioadenosine (MTA). Increased intratumoral MTA levels result from a lack of the MTA-catabolizing enzyme methylthioadenosine phosphorylase (MTAP) in tumor cells and are found in various tumor entities. Here, we demonstrate that MTA suppresses proliferation, activation, differentiation, and effector function of antigen-specific T cells without eliciting cell death...
August 2016: Oncoimmunology
Min Zhao, Zhongming Zhao
BACKGROUND: Tumor suppressor genes (TSGs) encode the guardian molecules to control cell growth. The genomic alteration of TSGs may cause tumorigenesis and promote cancer progression. So far, investigators have mainly studied the functional effects of somatic single nucleotide variants in TSGs. Copy number variation (CNV) is another important form of genetic variation, and is often involved in cancer biology and drug treatment, but studies of CNV in TSGs are less represented in literature...
2016: BMC Genomics
Carlos Stambolsky, Soledad Rodríguez-Benítez, José Luis Gutiérrez-Pérez, Daniel Torres-Lagares, Jenifer Martín-González, Juan José Segura-Egea
INTRODUCTION: This study evaluates histologically the efficacy of 4 revascularization protocols in necrotic-infected immature dog teeth with apical periodontitis (AP). METHODS: Forty double-rooted immature premolar teeth from 4 female Beagle dogs aged 5 months were used. Four teeth were left untouched as negative controls; the other 36 teeth were infected to develop pulp necrosis and AP. Four teeth were left untreated and assigned to the positive control group. The last 28 teeth were randomly assigned into four experimental groups of 8 teeth, each one treated with a different treatment protocol: A1, sodium hypochlorite (SH)+blood clot (BC); A2, SH+platelet-rich plasma (PRP); B1, SH+modified tri-antibiotic paste (mTAP)+BC; B2, SH+mTAP+PRP...
November 2016: Archives of Oral Biology
Katharina Limm, Katja Dettmer, Jörg Reinders, Peter J Oefner, Anja-Katrin Bosserhoff
Deficiency of methylthioadenosine phosphorylase (MTAP) supports melanoma development and progression through accumulation of its substrate 5'-methylthioadenosine (MTA), which leads amongst others to a constitutive inhibition of protein arginine methyltransferases (PRMTs) and activation of the transcription factor AP-1 via the receptor ADORA2B. Genetic association studies have also suggested that genetic polymorphism in MTAP may modulate the risk of melanoma. Here, we investigated the only globally common non-synonymous single nucleotide polymorphism (SNP) reported to date for MTAP...
2016: PloS One
Anastasiya V Snezhkina, George S Krasnov, Anastasiya V Lipatova, Asiya F Sadritdinova, Olga L Kardymon, Maria S Fedorova, Nataliya V Melnikova, Oleg A Stepanov, Andrew R Zaretsky, Andrey D Kaprin, Boris Y Alekseev, Alexey A Dmitriev, Anna V Kudryavtseva
Colorectal cancer is one of the most common cancers in the world. It is well known that the chronic inflammation can promote the progression of colorectal cancer (CRC). Recently, a number of studies revealed a potential association between colorectal inflammation, cancer progression, and infection caused by enterotoxigenic Bacteroides fragilis (ETBF). Bacterial enterotoxin activates spermine oxidase (SMO), which produces spermidine and H2O2 as byproducts of polyamine catabolism, which, in turn, enhances inflammation and tissue injury...
2016: Oxidative Medicine and Cellular Longevity
M L Nickerson, N Witte, K M Im, S Turan, C Owens, K Misner, S X Tsang, Z Cai, S Wu, M Dean, J C Costello, D Theodorescu
The utility of tumor-derived cell lines is dependent on their ability to recapitulate underlying genomic aberrations and primary tumor biology. Here, we sequenced the exomes of 25 bladder cancer (BCa) cell lines and compared mutations, copy number alterations (CNAs), gene expression and drug response to BCa patient profiles in The Cancer Genome Atlas (TCGA). We observed a mutation pattern associated with altered CpGs and APOBEC-family cytosine deaminases similar to mutation signatures derived from somatic alterations in muscle-invasive (MI) primary tumors, highlighting a major mechanism(s) contributing to cancer-associated alterations in the BCa cell line exomes...
June 6, 2016: Oncogene
Lucas Tadeu Bidinotto, Raul Torrieri, Alan Mackay, Gisele Caravina Almeida, Marta Viana-Pereira, Adriana Cruvinel-Carloni, Maria Luisa Spina, Nathalia Cristina Campanella, Weder Pereira de Menezes, Carlos Afonso Clara, Aline Paixão Becker, Chris Jones, Rui Manuel Reis
Copy number alterations (CNA) are one of the driving mechanisms of glioma tumorigenesis, and are currently used as important biomarkers in the routine setting. Therefore, we performed CNA profiling of 65 astrocytomas of distinct malignant grades (WHO grade I-IV) of Brazilian origin, using array-CGH and microsatellite instability analysis (MSI), and investigated their correlation with TERT and IDH1 mutational status and clinico-pathological features. Furthermore, in silico analysis using the Oncomine database was performed to validate our findings and extend the findings to gene expression level...
2016: G3: Genes—Genomes—Genetics
Katya Marjon, Michael J Cameron, Phong Quang, Michelle F Clasquin, Everton Mandley, Kaiko Kunii, Michael McVay, Sung Choe, Andrew Kernytsky, Stefan Gross, Zenon Konteatis, Joshua Murtie, Michelle L Blake, Jeremy Travins, Marion Dorsch, Scott A Biller, Kevin M Marks
Homozygous deletions of p16/CDKN2A are prevalent in cancer, and these mutations commonly involve co-deletion of adjacent genes, including methylthioadenosine phosphorylase (MTAP). Here, we used shRNA screening and identified the metabolic enzyme, methionine adenosyltransferase II alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. The MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss...
April 19, 2016: Cell Reports
Kamalakannan Palanichamy, Krishnan Thirumoorthy, Suman Kanji, Nicolaus Gordon, Rajbir Singh, John R Jacob, Nikhil Sebastian, Kevin T Litzenberg, Disha Patel, Emily Bassett, Brinda Ramasubramanian, Tim Lautenschlaeger, Steven M Fischer, Abhik Ray-Chaudhury, Arnab Chakravarti
PURPOSE: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma cells and tissues, with an aim toward identifying potential targetable biomarkers for developing more effective and novel therapies. EXPERIMENTAL DESIGN: We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established glioblastoma cells, glioblastoma tissues, and normal human astrocytes...
July 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Konstantinos J Mavrakis, E Robert McDonald, Michael R Schlabach, Eric Billy, Gregory R Hoffman, Antoine deWeck, David A Ruddy, Kavitha Venkatesan, Jianjun Yu, Gregg McAllister, Mark Stump, Rosalie deBeaumont, Samuel Ho, Yingzi Yue, Yue Liu, Yan Yan-Neale, Guizhi Yang, Fallon Lin, Hong Yin, Hui Gao, D Randal Kipp, Songping Zhao, Joshua T McNamara, Elizabeth R Sprague, Bing Zheng, Ying Lin, Young Shin Cho, Justin Gu, Kenneth Crawford, David Ciccone, Alberto C Vitari, Albert Lai, Vladimir Capka, Kristen Hurov, Jeffery A Porter, John Tallarico, Craig Mickanin, Emma Lees, Raymond Pagliarini, Nicholas Keen, Tobias Schmelzle, Francesco Hofmann, Frank Stegmeier, William R Sellers
5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity...
March 11, 2016: Science
Gregory V Kryukov, Frederick H Wilson, Jason R Ruth, Joshiawa Paulk, Aviad Tsherniak, Sara E Marlow, Francisca Vazquez, Barbara A Weir, Mark E Fitzgerald, Minoru Tanaka, Craig M Bielski, Justin M Scott, Courtney Dennis, Glenn S Cowley, Jesse S Boehm, David E Root, Todd R Golub, Clary B Clish, James E Bradner, William C Hahn, Levi A Garraway
The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A...
March 11, 2016: Science
Gaia Bistulfi, Hayley C Affronti, Barbara A Foster, Ellen Karasik, Bryan Gillard, Carl Morrison, James Mohler, James G Phillips, Dominic J Smiraglia
Prostatic epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen. This distinctive characteristic places added strain on the connected pathways, which are forced to increase metabolite production to maintain pools. The methionine salvage pathway recycles the one-carbon unit lost to polyamine biosynthesis back to the methionine cycle, allowing for replenishment of SAM pools providing a mechanism to help mitigate metabolic stress associated with high flux through these pathways...
March 22, 2016: Oncotarget
Huaping Xie, P Sivaramakrishna Rachakonda, Barbara Heidenreich, Eduardo Nagore, Antje Sucker, Kari Hemminki, Dirk Schadendorf, Rajiv Kumar
Genomic locus at chromosome 9p21 that contains the CDKN2A and CDKN2B tumor suppressor genes is inactivated through mutations, deletions and promoter methylation in multiple human cancers. Additionally, the locus encodes an anti-sense RNA (ANRIL). Both hemizygous and homozygous deletions at the locus targeting multiple genes are fairly common in different cancers. We in this study investigated breakpoints in five melanoma cell lines, derived from metastasized tumors, with previously identified homozygous deletions using array comparative genomic hybridization (aCGH)...
March 29, 2016: Oncotarget
Jossina Gonzalez, Desiree M Villarreal, Isaiah S Morales, Brian E Derrick
Hippocampal area CA1 receives direct entorhinal layer III input via the temporoammonic path (TAP) and recent studies implicate TAP-CA1 synapses are important for some aspects of hippocampal memory function. Nonetheless, as few studies have examined TAP-CA1 synaptic plasticity in vivo, the induction and longevity of TAP-CA1 long-term potentiation (LTP) has not been fully characterized. We analyzed CA1 responses following stimulation of the medial aspect of the angular bundle and investigated LTP at medial temporoammonic path (mTAP)-CA1 synapses in freely moving rats...
2016: Frontiers in Neural Circuits
(no author information available yet)
InMTAP-deficient cancer cells, PRMT5 expression and activity is preferentially required for cell growth.
April 2016: Cancer Discovery
Sanjay L Dholakiya, Angela Aliberti, Frank A Barile
Opioids have been shown to affect prenatal and postnatal neural development in mammals. The present study investigates the impact of morphine sulfate (MS) treatment on neuronal differentiation as well as μ-opioid receptor (MOR) expression in mouse embryonic stem (mES) cells. Stem cells were manipulated in culture to differentiate in 3 sequential stages: Stage 1, cell transformation to embryoid bodies (EB); Stage 2, EB cell differentiation to neural progenitor (NP) cells; and, Stage 3, NP cell differentiation to neurons/astrocytes co-cultured cells...
April 15, 2016: Toxicology Letters
Wesley J Woollard, Nithyha P Kalaivani, Christine L Jones, Catherine Roper, Lam Tung, Jae Jin Lee, Bjorn R Thomas, Isabella Tosi, Silvia Ferreira, Carl Z Beyers, Robert C T McKenzie, Rosie M Butler, Anna Lorenc, Sean J Whittaker, Tracey J Mitchell
Methylthioadenosine phosphorylase (MTAP) and the tumor suppressor genes CDKN2A-CDKN2B are frequently deleted in malignancies. The specific role of MTAP in cutaneous T-cell lymphoma subgroups, mycosis fungoides (MF) and Sézary syndrome (SS), is unknown. In 213 skin samples from patients with MF/SS, MTAP copy number loss (34%) was more frequent than CDKN2A (12%) in all cutaneous T-cell lymphoma stages using quantitative reverse transcription PCR. Importantly, in early stage MF, MTAP loss occurred independently of CDKN2A loss in 37% of samples...
June 2016: Journal of Investigative Dermatology
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