Thesis FINAL
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Gene Symbol Gene Description ACVR1B Activin a Receptor, Type IB
Table S1. Kinase clones included in human kinase cDNA library for yeast two-hybrid screening Gene Symbol Gene Description ACVR1B activin A receptor, type IB ADCK2 aarF domain containing kinase 2 ADCK4 aarF domain containing kinase 4 AGK multiple substrate lipid kinase;MULK AK1 adenylate kinase 1 AK3 adenylate kinase 3 like 1 AK3L1 adenylate kinase 3 ALDH18A1 aldehyde dehydrogenase 18 family, member A1;ALDH18A1 ALK anaplastic lymphoma kinase (Ki-1) ALPK1 alpha-kinase 1 ALPK2 alpha-kinase 2 AMHR2 anti-Mullerian hormone receptor, type II ARAF v-raf murine sarcoma 3611 viral oncogene homolog 1 ARSG arylsulfatase G;ARSG AURKB aurora kinase B AURKC aurora kinase C BCKDK branched chain alpha-ketoacid dehydrogenase kinase BMPR1A bone morphogenetic protein receptor, type IA BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) BRAF v-raf murine sarcoma viral oncogene homolog B1 BRD3 bromodomain containing 3 BRD4 bromodomain containing 4 BTK Bruton agammaglobulinemia tyrosine kinase BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) C9orf98 chromosome 9 open reading frame 98;C9orf98 CABC1 chaperone, ABC1 activity of bc1 complex like (S. pombe) CALM1 calmodulin 1 (phosphorylase kinase, delta) CALM2 calmodulin 2 (phosphorylase kinase, delta) CALM3 calmodulin 3 (phosphorylase kinase, delta) CAMK1 calcium/calmodulin-dependent protein kinase I CAMK2A calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha CAMK2B calcium/calmodulin-dependent -
Effect of STAT3 Inhibition on the Metabolic Switch in a Highly STAT3-Activated Lymphoma Cell Line
CANCER GENOMICS & PROTEOMICS 12 : 133-142 (2015) Effect of STAT3 Inhibition on the Metabolic Switch in a Highly STAT3-activated Lymphoma Cell Line YASUTO AKIYAMA 1* , AKIRA IIZUKA 1* , AKIKO KUME 1, MASARU KOMIYAMA 1, KENICHI URAKAMI 2, TADASHI ASHIZAWA 1, HARUO MIYATA 1, MAHO OMIYA 1, MASATOSHI KUSUHARA 3 and KEN YAMAGUCHI 4 1Immunotherapy Division, 2Cancer Diagnostics Division, 3Regional Resources Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, Japan; 4Office of the President, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan Abstract. Background: Signal transducer and activator of enzymes including fructose-bisphosphate aldolase A transcription (STAT)3 is involved in a metabolic shift in (ALDOA) as a metabolic marker candidate for STAT3- cancer cells, the Warburg effect through its pro-oncogenic targeting therapy using STAT3-specific shRNA gene activity. To develop efficient STAT3 inhibitors against cancer transduction. In particular, latexin expression was up- cells, novel proteomic and metabolic target molecules need regulated in four STAT3-activated cancer cell lines including to be explored using multi-omics approaches in the context of SCC-3 transduced with STAT3-specific shRNA. The up- STAT3 gene inhibition-mediated tumor growth suppression. regulation of latexin was identified in SCC-3 tumors Materials and Methods: We found that short hairpin transplanted to nude mice after treatment with STAT3 (sh)RNA-mediated STAT3 inhibition suppressed tumor inhibitor. Conclusion: Our results suggest that STAT3 growth in a highly STAT3-activated lymphoma cell line, inactivation reverses the glycolytic shift by down-regulating SCC-3 cells, and we investigated the effect of STAT3 key enzymes and that it induces up-regulation of latexin as a inhibition on metabolic switching using 2-dimensional tumor-suppressor molecule, which partially results in cancer differential gel electrophoresis and capillary electrophoresis- cell apoptosis and tumor growth suppression. -
Mtor Regulation of Metabolism in Hematologic Malignancies
cells Review mTOR Regulation of Metabolism in Hematologic Malignancies Simone Mirabilii 1 , Maria Rosaria Ricciardi 1 and Agostino Tafuri 1,2,* 1 Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy; [email protected] (S.M.); [email protected] (M.R.R.) 2 Hematology, “Sant’ Andrea” University Hospital, Sapienza University of Rome, 00185 Rome, Italy * Correspondence: [email protected]; Tel.: +39-06-3377-5113 Received: 6 December 2019; Accepted: 7 February 2020; Published: 11 February 2020 Abstract: Neoplastic cells rewire their metabolism, acquiring a selective advantage over normal cells and a protection from therapeutic agents. The mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular activities, including the control of metabolic processes. mTOR is hyperactivated in a large number of tumor types, and among them, in many hematologic malignancies. In this article, we summarized the evidence from the literature that describes a central role for mTOR in the acquisition of new metabolic phenotypes for different hematologic malignancies, in concert with other metabolic modulators (AMPK, HIF1α) and microenvironmental stimuli, and shows how these features can be targeted for therapeutic purposes. Keywords: mTOR; hematologic malignancies; cell metabolism 1. mTOR Structure and Function The mammalian Target of Rapamycin (mTOR) is a kinase involved in the PI3k/PTEN/Akt axis, which plays a key role in the control of many biological processes, including cell growth and survival, protein translation, ribosomal biogenesis, autophagy, and metabolism [1–3]. Originally identified in the yeast Saccharomyces cerevisiae, mTOR is a pleiotropic serine/threonine kinase of 289kDa, which shows a terminal COOH catalytic domain with a high sequence homology with PI3K [4]. -
Structures, Functions, and Mechanisms of Filament Forming Enzymes: a Renaissance of Enzyme Filamentation
Structures, Functions, and Mechanisms of Filament Forming Enzymes: A Renaissance of Enzyme Filamentation A Review By Chad K. Park & Nancy C. Horton Department of Molecular and Cellular Biology University of Arizona Tucson, AZ 85721 N. C. Horton ([email protected], ORCID: 0000-0003-2710-8284) C. K. Park ([email protected], ORCID: 0000-0003-1089-9091) Keywords: Enzyme, Regulation, DNA binding, Nuclease, Run-On Oligomerization, self-association 1 Abstract Filament formation by non-cytoskeletal enzymes has been known for decades, yet only relatively recently has its wide-spread role in enzyme regulation and biology come to be appreciated. This comprehensive review summarizes what is known for each enzyme confirmed to form filamentous structures in vitro, and for the many that are known only to form large self-assemblies within cells. For some enzymes, studies describing both the in vitro filamentous structures and cellular self-assembly formation are also known and described. Special attention is paid to the detailed structures of each type of enzyme filament, as well as the roles the structures play in enzyme regulation and in biology. Where it is known or hypothesized, the advantages conferred by enzyme filamentation are reviewed. Finally, the similarities, differences, and comparison to the SgrAI system are also highlighted. 2 Contents INTRODUCTION…………………………………………………………..4 STRUCTURALLY CHARACTERIZED ENZYME FILAMENTS…….5 Acetyl CoA Carboxylase (ACC)……………………………………………………………………5 Phosphofructokinase (PFK)……………………………………………………………………….6 -
Prioritization of Metabolic Genes As Novel Therapeutic Targets in Estrogen-Receptor Negative Breast Tumors Using Multi-Omics Data and Text Mining
www.oncotarget.com Oncotarget, 2019, Vol. 10, (No. 39), pp: 3894-3909 Research Paper Prioritization of metabolic genes as novel therapeutic targets in estrogen-receptor negative breast tumors using multi-omics data and text mining Dinesh Kumar Barupal1,*, Bei Gao1,*, Jan Budczies2, Brett S. Phinney4, Bertrand Perroud4, Carsten Denkert2,3 and Oliver Fiehn1 1West Coast Metabolomics Center, University of California, Davis, CA, USA 2Institute of Pathology, Charité University Hospital, Berlin, Germany 3German Institute of Pathology, Philipps-University Marburg, Marburg, Germany 4UC Davis Genome Center, University of California, Davis, CA, USA *Co-first authors and contributed equally to this work Correspondence to: Oliver Fiehn, email: [email protected] Keywords: set-enrichment; ChemRICH; multi-omics; metabolic networks; candidate gene prioritization Received: March 12, 2019 Accepted: May 13, 2019 Published: June 11, 2019 Copyright: Barupal et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Estrogen-receptor negative (ERneg) breast cancer is an aggressive breast cancer subtype in the need for new therapeutic options. We have analyzed metabolomics, proteomics and transcriptomics data for a cohort of 276 breast tumors (MetaCancer study) and nine public transcriptomics datasets using univariate statistics, meta- analysis, Reactome pathway analysis, biochemical network mapping and text mining of metabolic genes. In the MetaCancer cohort, a total of 29% metabolites, 21% proteins and 33% transcripts were significantly different (raw p <0.05) between ERneg and ERpos breast tumors. -
Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia
cancers Article Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia Miriam G. Contreras Mostazo 1,2,3, Nina Kurrle 3,4,5, Marta Casado 6,7 , Dominik Fuhrmann 8, Islam Alshamleh 4,9, Björn Häupl 3,4,5, Paloma Martín-Sanz 7,10, Bernhard Brüne 5,8,11 , 3,4,5 4,9 3,4,5, 1,2,7,12, , Hubert Serve , Harald Schwalbe , Frank Schnütgen y , Silvia Marin * y 1,2,7,12, , and Marta Cascante * y 1 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain; [email protected] 2 Institute of Biomedicine of University of Barcelona, 08028 Barcelona, Spain 3 Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; [email protected] (N.K.); [email protected] (B.H.); [email protected] (H.S.); [email protected] (F.S.) 4 German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; [email protected] (I.A.); [email protected] (H.S.) 5 Frankfurt Cancer Institute (FCI), Goethe University, 60590 Frankfurt am Main, Germany; [email protected] 6 Biomedicine Institute of Valencia, IBV-CSIC, 46010 Valencia, Spain; [email protected] 7 CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain; [email protected] 8 Institute of Biochemistry I, Faculty of -
California State University, Northridge
CALIFORNIA STATE UNIVERSITY, NORTHRIDGE Effects of Silencing Lipoprotein Lipase on Metabolic Enzymes in Rat Muscle Cells A thesis submitted in partial fulfillment of the requirements For the degree of Master of Science in Biochemistry By Adam Scott Mogul May 2019 The thesis of Adam Mogul is approved: ______________________________________ _____________________ Dr. Simon Garrett Date ______________________________________ _____________________ Dr. Daniel Tamae Date ______________________________________ _____________________ Dr. Jheem Medh, Chair Date California State University, Northridge ii Acknowledgements I would like to thank everyone in the CSUN Chemistry and Biochemistry department for helping me along this journey, especially those of you that helped supply me with helpful tips, reagents, or buffer solutions in my times of dire need. All of my friends in the department, the graduate and undergraduate students that have made my time at CSUN so enjoyable. The great group of people that have been a part of Dr. Medh’s lab, both past and present. Finally, a heartfelt thank you to Dr. Medh, for all of the help, understanding, and support through the time that I have spent in this program. Your guidance and patience have provided the foundation for my successful navigation of the world of biochemistry, and I truly appreciate it. iii Dedication I would like to dedicate this thesis to my Mom and Dad, who have believed in me and supported me through my academic career and beyond. To my grandparents, who have genuinely tried to be interested when I talk about my research, and provided me with love, food, and a place to sleep near school on late nights. -
Glucose Catabolism in Liver Tumors Induced by C-MYC Can Be
Published OnlineFirst June 19, 2017; DOI: 10.1158/0008-5472.CAN-17-0498 Cancer Tumor and Stem Cell Biology Research Glucose Catabolism in Liver Tumors Induced by c-MYC Can Be Sustained by Various PKM1/PKM2 Ratios and Pyruvate Kinase Activities Andres Mendez-Lucas 1, Xiaolei Li2,3, Junjie Hu2,4, Li Che2, Xinhua Song2, Jiaoyuan Jia2,5, Jingxiao Wang2, Chencheng Xie2,6, Paul C. Driscoll1, Darjus F. Tschaharganeh7,8, Diego F. Calvisi9, Mariia Yuneva1, and Xin Chen2,4 Abstract Different pyruvate kinase isoforms are expressed in a tissue- tumorigenesis and resulted in liver tumor formation with specific manner, with pyruvate kinase M2 (PKM2) suggested to decreased pyruvate kinase activity and decreased catabolism be the predominant isoform in proliferating cells and cancer of glucose into alanine and the Krebs cycle. An increased PKM1/ cells. Because of differential regulation of enzymatic activities, PKM2 ratio by ectopic PKM1 expression further decreased PKM2, but not PKM1, has been thought to favor cell prolifer- glucose flux into serine biosynthesis and increased flux into ation. However, the role of PKM2 in tumorigenesis has been lactate and the Krebs cycle, resulting in reduced total levels of recently challenged. Here we report that increased glucose serine. However, these changes also did not affect c-MYC– catabolism through glycolysis and increased pyruvate kinase induced liver tumor development. These results suggest that activity in c-MYC-driven liver tumors are associated with increased expression of PKM2 is not required to support increased expression of both PKM1 and PKM2 isoforms and c-MYC–induced tumorigenesis in the liver and that various decreased expression of the liver-specific isoform of pyruvate PKM1/PKM2 ratios and pyruvate kinase activities can sustain kinase, PKL. -
Bioenergetic Abnormalities in Schizophrenia
Bioenergetic abnormalities in schizophrenia A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate Program in Neuroscience of the College of Medicine by Courtney René Sullivan B.S. University of Pittsburgh, 2013 Dissertation Committee: Mark Baccei, Ph.D. (chair) Robert McCullumsmith, M.D., Ph.D. (advisor) Michael Lieberman, Ph.D. Temugin Berta, Ph.D. Robert McNamara, Ph.D. ABSTRACT Schizophrenia is a devastating illness that affects over 2 million people in the U.S. and displays a wide range of psychotic symptoms, as well as cognitive deficits and profound negative symptoms that are often treatment resistant. Cognition is intimately related to synaptic function, which relies on the ability of cells to obtain adequate amounts of energy. Studies have shown that disrupting bioenergetic pathways affects working memory and other cognitive behaviors. Thus, investigating bioenergetic function in schizophrenia could provide important insights into treatments or prevention of cognitive disorders. There is accumulating evidence of bioenergetic dysfunction in chronic schizophrenia, including deficits in energy storage and usage in the brain. However, it is unknown if glycolytic pathways are disrupted in this illness. This dissertation employs a novel reverse translational approach to explore glycolytic pathways in schizophrenia, effectively combining human postmortem studies with bioinformatic analyses to identify possible treatment strategies, which we then examine in an animal model. To begin, we characterized a major pathway supplying energy to neurons (the lactate shuttle) in the dorsolateral prefrontal cortex (DLPFC) in chronic schizophrenia. We found a significant decrease in the activity of two key glycolytic enzymes in schizophrenia (hexokinase, HXK and phosphofructokinase, PFK), suggesting a decrease in the capacity to generate bioenergetic intermediates through glycolysis in this illness. -
Nonsense Mutation in the Phosphofructokinase Muscle
Proc. Natl. Acad. Sci. USA Vol. 92, pp. 10322-10326, October 1995 Medical Sciences Nonsense mutation in the phosphofructokinase muscle subunit gene associated with retention of intron 10 in one of the isolated transcripts in Ashkenazi Jewish patients with Tarui disease (glycogenosis type VII/phosphofructokinase deficiency/human PFKM gene) OLAVO VASCONCELOS*, KUMARASWAMY SIVAKUMARt, MARINOS C. DALAKASt, MARTHA QUEZADOt, JAMES NAGLE*, MARTA LEON-MONZONt, MARK DUBNICK*, D. CARLETON GAJDUSEK§, AND LEV G. GOLDFARB* *Clinical Neurogenetics Unit and tNeuromuscular Diseases Section, Medical Neurology Branch, §Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, and tLaboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Contributed by D. Carleton Gajdusek, June 28, 1995 ABSTRACT Mutations in the human phosphofructoki- infirmity requires biochemical assays in skeletal muscle (11). nase muscle subunit gene (PFKAM) are known to cause myop- The condition has been described in a number of Ashkenazi athy classified as glycogenosis type VII (Tarui disease). Pre- Jewish families as well as in non-Ashkenazi pedigrees of viously described molecular defects include base substitutions Japanese, Italian, Swiss, and French Canadian origins (12-17). altering encoded amino acids or resulting in abnormal splic- Recent studies have led to the identification of 11 alleles ing. We report a mutation resulting in phosphofructokinase associated with PFK deficiency (Table 1). deficiency in three patients from an Ashkenazi Jewish family. We studied three patients from an Ashkenazi Jewish family Using a reverse transcription PCR assay, PFKM subunit of Polish origin having an inherited myopathy combined with transcripts differing by length were detected in skeletal mus- recurrent compensated hemolysis. -
Identification of Genes Directly Responding to DLK1 Signaling in Callipyge Sheep Hui Yu1,2* ,Jolenan.Waddell1,6, Shihuan Kuang1,3, Ross L
Yu et al. BMC Genomics (2018) 19:283 https://doi.org/10.1186/s12864-018-4682-1 RESEARCH ARTICLE Open Access Identification of genes directly responding to DLK1 signaling in Callipyge sheep Hui Yu1,2* ,JolenaN.Waddell1,6, Shihuan Kuang1,3, Ross L. Tellam4,NoelleE.Cockett5 and Christopher A. Bidwell1* Abstract Background: In food animal agriculture, there is a need to identify the mechanisms that can improve the efficiency of muscle growth and protein accretion. Callipyge sheep provide excellent machinery since the up-regulation of DLK1 and RTL1 results in extreme postnatal muscle hypertrophy in distinct muscles. The aim of this study is to distinguish the genes that directly respond to DLK1 and RTL1 signaling from the genes that change as the result of muscle specific effects. Results: The quantitative PCR results indicated that DLK1 expression was significantly increased in hypertrophied muscles but not in non-hypertrophied muscles. However, RTL1 was up-regulated in both hypertrophied and non- hypertrophied muscles. Five genes, including PARK7, DNTTIP1, SLC22A3, METTL21E and PDE4D, were consistently co- expressed with DLK1, and therefore were possible transcriptional target genes responding to DLK1 signaling. Treatment of myoblast and myotubes with DLK1 protein induced an average of 1.6-fold and 1.4-fold increase in Dnttip1 and Pde4d expression respectively. Myh4 expression was significantly elevated in DLK1-treated myotubes, whereas the expression of Mettl21e was significantly increased in the DLK1-treated myoblasts but reduced in DLK1- treated myotubes. DLK1 treatment had no impact on Park7 expression. In addition, Park7 and Dnttip1 increased Myh4 and decreased Myh7 promoter activity, resemble to the effects of Dlk1. -
Insulin Resistance Related Signaling Pathways in the Liver
INSULIN RESISTANCE RELATED SIGNALING PATHWAYS IN THE LIVER by Yuchun Wang A thesis submitted to Johns Hopkins University in conformity with the requirements for the degree of Master of Science in Engineering Baltimore, Maryland May, 2020 © 2020 Yuchun Wang All rights reserved Abstract Over the past 20 years, the worldwide toll of diabetes has tripled to more than 400 million, which makes it one of the fastest-growing health challenges of the 21st century. There are three main categories of diabetes: type 1, type 2 and gestational diabetes mellitus. Among them, Type 2 diabetes(T2D) makes up to 90% of diabetes worldwide. Hyper- glycemia can be effectively controlled by giving insulin injection for type 1 and gestational diabetes mellitus. However, because insulin resistance is one of the causes of T2D, those with T2D do not respond as well to insulin as those with T1D or gestational diabetes. Fur- thermore, our lack of knowledge about the underlying physiology of T2D makes it difficult to find reliable treatments. While high blood glucose concentration is one of the major symptoms of T2D, changes in lipid metabolism are characteristic of insulin resistance(IR). In the human body, the liver plays a major role in glucose homeostasis and lipid metabolism. Hence, this essay pro- vides an overview of signaling pathways in the liver and presents their interrelationship to better understand the underlying IR mechanism. Primary Reader and Advisor: Marc D. Donohue Secondary Reader: Gregory Aranovich ii Acknowledgements I wish to express my deepest gratitude to my advisor, Professor Marc D. Donohue, for introducing me to the fantastic world of science, and for his patient guidance along the road of my Master’s study.