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The Landscape of Cancer Cell Line Metabolism
The Landscape of Cancer Cell Line Metabolism The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Li, Haoxin, Shaoyang Ning, Mahmoud Ghandi, Gregory V. Kryukov, Shuba Gopal, Amy Deik, Amanda Souza, et. al. 2019. The Landscape of Cancer Cell Line Metabolism. Nature Medicine 25, no. 5: 850-860. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:41899268 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nat Med Manuscript Author . Author manuscript; Manuscript Author available in PMC 2019 November 08. Published in final edited form as: Nat Med. 2019 May ; 25(5): 850–860. doi:10.1038/s41591-019-0404-8. The Landscape of Cancer Cell Line Metabolism Haoxin Li1,2, Shaoyang Ning3, Mahmoud Ghandi1, Gregory V. Kryukov1, Shuba Gopal1, Amy Deik1, Amanda Souza1, Kerry Pierce1, Paula Keskula1, Desiree Hernandez1, Julie Ann4, Dojna Shkoza4, Verena Apfel5, Yilong Zou1, Francisca Vazquez1, Jordi Barretina4, Raymond A. Pagliarini4, Giorgio G. Galli5, David E. Root1, William C. Hahn1,2, Aviad Tsherniak1, Marios Giannakis1,2, Stuart L. Schreiber1,6, Clary B. Clish1,*, Levi A. Garraway1,2,*, and William R. Sellers1,2,* 1Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA 2Department -
The Aldehyde Dehydrogenase ALDH2*2 Allele Exhibits Dominance Over ALDH2*1 in Transduced Hela Cells
The aldehyde dehydrogenase ALDH2*2 allele exhibits dominance over ALDH2*1 in transduced HeLa cells. Q Xiao, … , T Johnston, D W Crabb J Clin Invest. 1995;96(5):2180-2186. https://doi.org/10.1172/JCI118272. Research Article Individuals heterozygous or homozygous for the variant aldehyde dehydrogenase (ALDH2) allele (ALDH2*2), which encodes a protein differing only at residue 487 from the normal protein, have decreased ALDH2 activity in liver extracts and experience cutaneous flushing when they drink alcohol. The mechanisms by which this allele exerts its dominant effect is unknown. To study this effect, the human ALDH2*1 cDNA was cloned and the ALDH2*2 allele was generated by site-directed mutagenesis. These cDNAs were transduced using retroviral vectors into HeLa and CV1 cells, which do not express ALDH2. The normal allele directed synthesis of immunoreactive ALDH2 protein (ALDH2E) with the expected isoelectric point. Extracts of these cells contained increased aldehyde dehydrogenase activity with low Km for the aldehyde substrate. The ALDH2*2 allele directed synthesis of mRNA and immunoreactive protein (ALDH2K), but the protein lacked enzymatic activity. When ALDH2*1-expressing cells were transduced with ALDH2*2 vectors, both mRNAs were expressed and immunoreactive proteins with isoelectric points ranging between those of ALDH2E and ALDH2K were present, indicating that the subunits formed heteromers. ALDH2 activity in these cells was reduced below that of the parental ALDH2*1-expressing cells. Thus, the ALDH2*2 allele is sufficient to cause ALDH2 deficiency in vitro. Find the latest version: https://jci.me/118272/pdf The Aldehyde Dehydrogenase ALDH2*2 Allele Exhibits Dominance over ALDH2*1 in Transduced HeLa Cells Qing Xiao, * Henry Weiner,* Timothy Johnston,* and David W. -
The Role of Polyamine Uptake Transporters on Growth and Development of Arabidopsis Thaliana
THE ROLE OF POLYAMINE UPTAKE TRANSPORTERS ON GROWTH AND DEVELOPMENT OF ARABIDOPSIS THALIANA Jigarkumar Patel A Dissertation Submitted to the Graduate College of Bowling Green State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY May 2015 Committee: Paul Morris, Advisor Wendy D Manning Graduate Faculty Representative Vipaporn Phuntumart Scott Rogers Ray Larsen © 2015 Jigarkumar Patel All Rights Reserved iii ABSTRACT Paul Morris, Advisor Transgenic manipulation of polyamine levels has provided compelling evidence that polyamines enable plants to respond to environmental cues by activation of stress and developmental pathways. Here we show that the chloroplasts of A. thaliana and soybeans contain both an arginine decarboxylase, and an arginase/agmatinase. These two enzymes combine to synthesize putrescine from arginine. Since the sequences of plant arginases show conservation of key residues and the predicted 3D structures of plant agmatinases overlap the crystal structure of the enzyme from Deinococcus radiodurans, we suggest that these enzymes can synthesize putrescine, whenever they have access to the substrate agmatine. Finally, we show that synthesis of putrescine by ornithine decarboxylase takes place in the ER. Thus A. thaliana has two, and soybeans have three separate pathways for the synthesis of putrescine. This study also describes key changes in plant phenotypes in response to altered transport of polyamines. iv Dedicated to my father, Jayantilal Haribhai Patel v ACKNOWLEDGMENTS I would like to thank my advisor, Dr. Paul F. Morris, for helping me learn and grow during my Ph.D. Dr. Morris has an open door policy, and he was always available to answer my questions and provide helpful suggestions. -
Integrative Pathway Analysis of Metabolic Signature in Bladder Cancer: a Linkage to the Cancer Genome Atlas Project and Prediction of Survival
Integrative Pathway Analysis of Metabolic Signature in Bladder Cancer: A Linkage to The Cancer Genome Atlas Project and Prediction of Survival Friedrich-Carl von Rundstedt,* Kimal Rajapakshe,* Jing Ma, James M. Arnold, Jie Gohlke, Vasanta Putluri, Rashmi Krishnapuram, D. Badrajee Piyarathna, Yair Lotan, Daniel Godde,€ Stephan Roth, Stephan Storkel,€ Jonathan M. Levitt, George Michailidis, Arun Sreekumar, Seth P. Lerner, Cristian Coarfa† and Nagireddy Putluri† From the Scott Department of Urology (FCvR, JML, SPL), Department of Molecular and Cell Biology, Alkek Center for Molecular Discovery (KR, JMA, JG, RK, DBP, AS, CC, NP), Verna and Marrs McLean Department of Biochemistry (AS), Advanced Technology Core (VP, DBP, AS, NP) and Department of Pathology and Immunology (JML), Baylor College of Medicine, Houston and Department of Urology, University of Texas Southwestern Medical Center (YL), Dallas, Texas, Departments of Urology (FCvR, SR) and Pathology Helios Klinikum (DG, SS), Witten-Herdecke University, Wuppertal, Germany, and Department of Statistics, University of Michigan (JM, GM), Ann Arbor, Michigan Purpose: We used targeted mass spectrometry to study the metabolic fingerprint of urothelial cancer and determine whether the biochemical pathway analysis Abbreviations and Acronyms gene signature would have a predictive value in independent cohorts of patients ¼ with bladder cancer. BCa bladder cancer Materials and Methods: Pathologically evaluated, bladder derived tissues, including benign adjacent tissue from 14 patients and bladder cancer from 46, were analyzed by liquid chromatography based targeted mass spectrometry. Differen- tial metabolites associated with tumor samples in comparison to benign tissue were identified by adjusting the p values for multiple testing at a false discovery rate threshold of 15%. -
RT² Profiler PCR Array (Rotor-Gene® Format) Human Amino Acid Metabolism I
RT² Profiler PCR Array (Rotor-Gene® Format) Human Amino Acid Metabolism I Cat. no. 330231 PAHS-129ZR For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Rotor-Gene Q, other Rotor-Gene cyclers Format R Description The Human Amino Acid Metabolism I RT² Profiler PCR Array profiles the expression of 84 key genes important in biosynthesis and degradation of functional amino acids. Of the 20 amino acids required for protein synthesis, six of them (arginine, cysteine, glutamine, leucine, proline, and tryptophan), collectively known as the functional amino acids, regulate key metabolic pathways involved in cellular growth, and development, as well as other important biological processes such as immunity and reproduction. For example, leucine activates mTOR signaling and increases protein synthesis, leading to lymphocyte proliferation. Therefore, a lack of leucine can compromise immune function. Metabolic pathways interrelated with the biosynthesis and degradation of these amino acids include vitamin and cofactor biosynthesis (such as SAM or S-Adenosyl Methionine) as well as neurotransmitter metabolism (such as glutamate). This array includes genes for mammalian functional amino acid metabolism as well as genes involved in methionine metabolism, important also for nutrient sensing and sulfur metabolism. Using realtime PCR, you can easily and reliably analyze the expression of a focused panel of genes involved in functional amino acid metabolism with this array. For further details, consult the RT² Profiler PCR Array Handbook. Shipping and storage RT² Profiler PCR Arrays in the Rotor-Gene format are shipped at ambient temperature, on dry ice, or blue ice packs depending on destination and accompanying products. -
Expression and Characterization of Pantoea CO Dehydrogenase To
www.nature.com/scientificreports OPEN Expression and characterization of Pantoea CO dehydrogenase to utilize CO-containing industrial Received: 31 October 2016 Accepted: 06 February 2017 waste gas for expanding the Published: 14 March 2017 versatility of CO dehydrogenase Eun Sil Choi1,2,*, Kyoungseon Min3,*, Geun-Joong Kim2, Inchan Kwon1 & Yong Hwan Kim3 Although aerobic CO dehydrogenases (CODHs) might be applicable in various fields, their practical applications have been hampered by low activity and no heterologous expression. We, for the first time, could functionally express recombinant PsCODH in E. coli and obtained a highly concentrated recombinant enzyme using an easy and convenient method. Its electron acceptor spectra, optimum −1 conditions (pH 6.5 and 30 °C), and kinetic parameters (kcat of 12.97 s , Km of 0.065 mM, and specific activity of 0.86 Umg−1) were examined. Blast furnace gas (BFG) containing 20% CO, which is a waste gas from the steel-making process, was tested as a substrate for PsCODH. Even with BFG, the recombinant PsCODH retained 88.2% and 108.4% activity compared with those of pure CO and 20% CO, respectively. The results provide not only a promising strategy to utilize CO-containing industrial waste gases as cheap, abundant, and renewable resources but also significant information for further studies about cascade reactions producing value-added chemicals via CO2 as an intermediate produced by a CODH- based CO-utilization system, which would ultimately expand the versatility of CODH. Carbon monoxide (CO), which is a pollutant in the atmosphere, is massively emitted through both natural (e.g., production by plants and volcanic activity) and artificial processes (e.g., incomplete combustion of fuels and industrial processes)1–3. -
The Evolution and Population Genetics of the ALDH2 Locus: Random Genetic Drift, Selection, and Low Levels of Recombination
doi: 10.1046/j.1529-8817.2003.00060.x The evolution and population genetics of the ALDH2 locus: random genetic drift, selection, and low levels of recombination Hiroki Oota1, Andrew J. Pakstis1, Batsheva Bonne-Tamir2, David Goldman3, Elena Grigorenko4, Sylvester L. B. Kajuna5, Nganyirwa J. Karoma5, Selemani Kungulilo6, Ru-Band Lu7, Kunle Odunsi8, Friday Okonofua9, Olga V. Zhukova10, Judith R. Kidd1 and Kenneth K. Kidd1,∗ 1Department of Genetics, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208005, New Haven, CT 06520-8005, USA 2Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 3Laboratory of Neurogenetics, National Institute of Alcohol Abuse and Alcoholism, Rockville, MD 20852, USA 4Department of Psychology, Yale University, New Haven, CT 06520, USA 5The Hubert Kairuki Memorial University, Dar es Salaam, Tanzania 6Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania 7Department of Psychiatry, Tri-Service General hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C. 8Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 9Department of Obstetrics and Gynecology, Faculty of Medicine, University of Benin, Benin City, Nigeria 10N.I. Vavilov Institute of General Genetics RAS, Moscow, Russia Summary The catalytic deficiency of human aldehyde dehydrogenase 2 (ALDH2) is caused by a nucleotide substitution (G1510A; Glu487Lys) in exon 12 of the ALDH2 locus. This SNP,and four non-coding SNPs, including one in the promoter, span 40 kb of ALDH2; these and one downstream STRP have been tested in 37 worldwide populations. Only four major SNP-defined haplotypes account for almost all chromosomes in all populations. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
How Is Alcohol Metabolized by the Body?
Overview: How Is Alcohol Metabolized by the Body? Samir Zakhari, Ph.D. Alcohol is eliminated from the body by various metabolic mechanisms. The primary enzymes involved are aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), cytochrome P450 (CYP2E1), and catalase. Variations in the genes for these enzymes have been found to influence alcohol consumption, alcohol-related tissue damage, and alcohol dependence. The consequences of alcohol metabolism include oxygen deficits (i.e., hypoxia) in the liver; interaction between alcohol metabolism byproducts and other cell components, resulting in the formation of harmful compounds (i.e., adducts); formation of highly reactive oxygen-containing molecules (i.e., reactive oxygen species [ROS]) that can damage other cell components; changes in the ratio of NADH to NAD+ (i.e., the cell’s redox state); tissue damage; fetal damage; impairment of other metabolic processes; cancer; and medication interactions. Several issues related to alcohol metabolism require further research. KEY WORDS: Ethanol-to acetaldehyde metabolism; alcohol dehydrogenase (ADH); aldehyde dehydrogenase (ALDH); acetaldehyde; acetate; cytochrome P450 2E1 (CYP2E1); catalase; reactive oxygen species (ROS); blood alcohol concentration (BAC); liver; stomach; brain; fetal alcohol effects; genetics and heredity; ethnic group; hypoxia The alcohol elimination rate varies state of liver cells. Chronic alcohol con- he effects of alcohol (i.e., ethanol) widely (i.e., three-fold) among individ- sumption and alcohol metabolism are on various tissues depend on its uals and is influenced by factors such as strongly linked to several pathological concentration in the blood T chronic alcohol consumption, diet, age, consequences and tissue damage. (blood alcohol concentration [BAC]) smoking, and time of day (Bennion and Understanding the balance of alcohol’s over time. -
The Genetics of Bipolar Disorder
Molecular Psychiatry (2008) 13, 742–771 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp FEATURE REVIEW The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions A Serretti and L Mandelli Institute of Psychiatry, University of Bologna, Bologna, Italy Bipolar disorder (BP) is a complex disorder caused by a number of liability genes interacting with the environment. In recent years, a large number of linkage and association studies have been conducted producing an extremely large number of findings often not replicated or partially replicated. Further, results from linkage and association studies are not always easily comparable. Unfortunately, at present a comprehensive coverage of available evidence is still lacking. In the present paper, we summarized results obtained from both linkage and association studies in BP. Further, we indicated new potential interesting genes, located in genome ‘hot regions’ for BP and being expressed in the brain. We reviewed published studies on the subject till December 2007. We precisely localized regions where positive linkage has been found, by the NCBI Map viewer (http://www.ncbi.nlm.nih.gov/mapview/); further, we identified genes located in interesting areas and expressed in the brain, by the Entrez gene, Unigene databases (http://www.ncbi.nlm.nih.gov/entrez/) and Human Protein Reference Database (http://www.hprd.org); these genes could be of interest in future investigations. The review of association studies gave interesting results, as a number of genes seem to be definitively involved in BP, such as SLC6A4, TPH2, DRD4, SLC6A3, DAOA, DTNBP1, NRG1, DISC1 and BDNF. -
Ornithine Decarboxylase Regulates M1 Macrophage Activation And
Ornithine decarboxylase regulates M1 macrophage PNAS PLUS activation and mucosal inflammation via histone modifications Dana M. Hardbowera,b, Mohammad Asimb, Paula B. Luisc, Kshipra Singhb, Daniel P. Barryb, Chunying Yangd,e, Meredith A. Steevese, John L. Clevelandd,e, Claus Schneiderc, M. Blanca Piazuelob, Alain P. Gobertb, and Keith T. Wilsona,b,f,g,h,1 aDepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; bDivision of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; cDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232; dDepartment of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612; eDepartment of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458; fDepartment of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; gCenter for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN 37232; and hVeterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37232 Edited by Carl F. Nathan, Weill Medical College of Cornell University, New York, NY, and approved December 20, 2016 (received for review September 6, 2016) Macrophage activation is a critical step in host responses during pathogens is macrophage activation. Macrophages have the ca- bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting pacity to alter cytokine/chemokine production and various other enzyme in polyamine metabolism, has been well studied in epithelial functions along the spectrum of M1 or M2 activation based on the cells and is known to have essential roles in many different cellular stimulus detected (12–14). M1 macrophages represent a highly functions. However, its role in regulating macrophage function during proinflammatory and antimicrobial subset of macrophages (12–14). -
Small-Molecule Binding Sites to Explore New Targets in the Cancer Proteome
Electronic Supplementary Material (ESI) for Molecular BioSystems. This journal is © The Royal Society of Chemistry 2016 Small-molecule binding sites to explore new targets in the cancer proteome David Xu, Shadia I. Jalal, George W. Sledge Jr., and Samy O. Meroueh* Supplementary Text Druggable Binding Sites across all 10 Diseases. Using the previously established cutoffs, we identified genes that were overexpressed across multiple cancer types and featured druggable binding sites. We ranked these genes based on the total number of tumors that overexpressed the gene (Fig. S1). Using a simple PubMed query, we then counted the number of articles in which either the gene symbol or gene name was co-mentioned with the term ‘cancer’. Most of the most frequently occurring differentially-expressed genes correspond to proteins of well- established cancer targets. Among them are matrix metalloproteinases (MMPs), including MMP1, MMP9, and MMP12, which are implicated in tumor invasion and metastasis (1). There are several protein kinases, including TTK, AURKA, AURKB, and PLK1, that are involved in cell signaling and well-established oncology targets (2). Some genes among this list that have not been extensively studied nor targeted in cancer. These include the serine/threonine kinase PKMYT1 (MYT1) is a regulator of G2/M transition in the cell cycle, but lacks focused small molecule inhibitors that specifically target the kinase. Recent efforts in developing small molecule inhibitors involve repurposing of available kinase inhibitors to specifically target the kinase (3). A subunit of the GINS complex GINS2 (PSF2) is involved in cell proliferation and survival in cancer cell lines (4,5).