DOCSLIB.ORG

The Sensitivity of Human Cells Expressing RUNX1-RUNX1T1 to Chemotherapeutic Agents

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Letters to the Editor 1883 The sensitivity of human cells expressing RUNX1-RUNX1T1 to chemotherapeutic agents Leukemia (2006) 20, 1883–1885. doi:10.1038/sj.leu.2404364; AML.1 The translocation involves DNA rearrangement of the published online 17 August 2006 RUNX1 (aka. AML1, core binding factor (CBFa)) gene on chromosome 21 with the RUNX1T1 (aka. ETO) gene on The translocation (8;21)(q22;q22) is observed in approximately chromosome 8. This abnormality leads to the expression of 12–15% of patients with acute myeloid leukaemia (AML), the RUNX1-RUNX1T1 (aka. AML1-ETO) fusion gene, which making it one of the most frequently observed translocations in promotes self-renewal of haematopoietic cells and also inhibits ab10 10 Control Control RUNX1-RUNX1T1 RUNX1-RUNX1T1 1 1 (log scale) (log scale) Normalised gene expression Normalised gene expression Normalised gene expression 0.1 0.1 TAP1 TAP2 TAP1 TAP2 ABCB1 ABCB6 ABCB7 ABCB1 ABCB6 ABCB7 CD34+ progenitor cells Monocytic progenitor cells (Day 3) (Day 6) c 10 d 10 Control Normal donors RUNX1-RUNX1T1 Other M2 t(8;21)-M2 1 1 (log scale) (log scale) Normalised gene expression Normalised gene expression Normalised gene expression Normalised gene expression 0.1 0.1 TAP1 TAP2 TAP1 TAP2 ABCB1 ABCB6 ABCB7 ABCB1 ABCB6 ABCB7 ABCB11 Granulocytic progenitor AML Patients cells (Day 6) Figure 1 For caption see page 1884. Leukemia Letters to the Editor 1884 a Control b Control c Control RUNX1-RUNX1T1 RUNX1-RUNX1T1 RUNX1-RUNX1T1 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40 20 20 20 % Viable cells (normalised to control) % Viable 0 cells (normalised to control) % Viable 0 cells (normalised to control) % Viable 0 0 10-1110-10 10-9 10-8 10-7 0 10-9 10-8 10-7 10-6 0 10-8 10-7 10-6 10-5 10-4 Daunorubicin Cytarabine Fludarabine concentration (M) concentration (M) concentration (M) de Control Control f Control RUNX1-RUNX1T1 RUNX1-RUNX1T1 RUNX1-RUNX1T1 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40 20 20 20 % Viable cells (normalised to control) % Viable % Viable cells (normalised to control) % Viable % Viable cells (normalised to control) % Viable 0 0 0 0 0 -9 -8 -9 -9 -9 -9 0 10-9 10-8 10-7 10-6 10 10 2×10 4×10 6×10 8×10 Idarubicin Etoposide concentration (M) concentration (M) Control Flu / Cyt Flu / Cyt Ida Dau / Cyt Dau / Cyt Eto Figure 2 Effect of chemotherapeutic drugs on the growth of human progenitor cells expressing RUNX1-RUNX1T1. Human CD34 þ cells transduced with RUNX1-RUNX1T1 were assayed 3 days after retroviral transduction (in comparison with matched cultures expressing GFP alone). The numbers of GFP þ PIÀ cells were scored by a calibrated flow cytometric assay (as described previously)2 after 2 days in culture treated with increasing doses of (a) Daunorubicin, Dau, (b) Cytarabine, Cyt, (c) Fludarabine, flu, (d) Idarubicin, Ida, (e)Etoposide,Etoor(f) combined drug treatment (using concentrations of drug that inhibited growth by 50%). Data indicate mean71 s.d. of a minimum of three independent replicate analyses. their subsequent differentiation.2 Leukaemias expressing this associated with multi-drug resistance (MDR) gene expres- abnormality are generally associated with a good prognosis in sion.4–6 The MDR-1 gene encodes P-glycoprotein, a cell terms of complete remission, relapse risk and overall survival membrane drug efflux pump. It would be envisaged that compared with other subtypes and tend to respond favourably to patients who are considered to have a good prognosis (such as treatment particularly with high-dose cytarabine and an t(8;21)) would not overexpress MDR-1 (as demonstrated by anthracycline.3 It is currently not known why patients expres- Lutterbach et al.4), otherwise it is likely those individuals would sing the t(8;21) have a good prognosis. The chemosensitivity of show chemoresistance and have a more adverse prognoses. patients with AML has previously been suggested to be Surprisingly, previous studies have found positive correlations Figure 1 MDR gene expression in cells with the RUNX1-RUNX1T1 fusion gene. RNA isolation and Affymetrix microarray analysis was performed on AML patients or human CD34 þ cells transduced with RUNX1-RUNX1T1 retrovirus coexpressing green fluorescent protein (GFP) (470% transduced). Cells expressing GFP alone were used as controls. (a) Day 3 human CD34 þ mixed progenitor cells (n ¼ 5), (b) day 6 transduced CD14hi monocytes (n ¼ 4), (c) day 6 transduced granulocytes cells (CD14lo, CD15hi, CD36lo; n ¼ 4) or (d) AML patients classified as FAB-M2 with (n ¼ 9) or without (n ¼ 29) the t(8;21). Data indicate the average normalized gene expression of MDR genes: TAP, ATP-binding cassette, sub-family B (MDR/TAP), transporter; ABCB1, ATP-binding cassette, sub-family B (MDR/TAP). (For figure see page 1883.) Leukemia Letters to the Editor 1885 between the t(8;21) karyotype and MDR-1 gene expression,5,6 expressing cells and t(8;21) patients,7,9 a protein that acts as a suggesting that this transcription factor fusion gene may promote tumour suppressor gene in other contexts. the expression of MDR-1. We therefore tested this hypothesis directly by expressing the RUNX1-RUNX1T1 fusion as a single abnormality in human haematopoietic cell subsets and per- Acknowledgements formed Affymetrix microarray analysis (as described pre- viously)2,7 to determine whether this fusion had any effect on We thank Amanda Gilkes and Megan Musson (Cardiff University) the transcription of MDR genes. Using this approach, we for their technical assistance in processing microarray samples. generated independent replicate sets of data from control and We are grateful to the MRC for access to patient sample material RUNX1-RUNX1T1-matched CD34 þ cultures as well as matched enrolled in the NCRI clinical trials. This work was supported by sets constituting granulocytic (CD14lo,CD36lo,CD15hi)and Leukaemia Research, UK. hi monocytic (CD14 ) unilineage populations (isolated from day 6 A Tonks1, L Pearn1, KI Mills1, AK Burnett1 and RL Darley1 cultures by immunomagnetic sorting). cRNA was prepared from 1Department of Haematology, School of Medicine, Cardiff each sample and hybridized to Affymetrix human 133A University, Cardiff, UK oligonucleotide arrays, which allowed the simultaneous analysis E-mail: [email protected] of six MDR family gene members. In each of these populations, the expression of MDR genes was not significantly different from References controls (Figure 1a–c). In addition, using our cohort of French– American–British (FAB)-M2 patients, there was little difference in 1 Peterson LF, Zhang DE. The 8;21 translocation in leukemogenesis. MDR gene expression between those individuals with a t(8;21) Oncogene 2004; 23: 4255–4262. and those without this abnormality (Figure 1d). We could 2 Tonks A, Tonks AJ, Pearn L, Pearce L, Hoy T, Couzens S et al. therefore find no evidence that RUNX1-RUNX1T1 expression Expression of AML1-ETO in human myelomonocytic cells selec- directly influences MDR gene expression as a single abnormality tively inhibits granulocytic differentiation and promotes their self- renewal. Leukemia 2004; 18: 1238–1245. or in t(8;21) patients. One alternative explanation for the 3 Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, aforementioned observations in AML patients is that other Harrison G et al. The importance of diagnostic cytogenetics on coexisting abnormalities may be influencing the expression of outcome in AML: analysis of 1612 patients entered into the MRC MDR, as suggested by Schaich et al.6 AML 10 trial. The Medical Research Council Adult and Children’s We next addressed the issue of whether the t(8;21) Leukaemia Working Parties. Blood 1998; 92: 2322–2333. abnormality directly influences the susceptibility to chemother- 4 Lutterbach B, Sun D, Schuetz J, Hiebert SW. The MYND motif is required for repression of basal transcription from the multidrug apeutic agents. We therefore assessed the sensitivity of normal resistance 1 promoter by the t(8;21) fusion protein. Mol Cell Biol human cells (expressing RUNX1-RUNX1T1 as a single abnorm- 1998; 18: 3604–3611. ality) to a number of drugs commonly used to treat AML 5 Pearson L, Leith CP, Duncan MH, Chen IM, McConnell T, Trinkaus (Daunorubicin, Cytarabine, Fludarabine, Idarubicin or Etopo- K et al. Multidrug resistance-1 (MDR1) expression and functional side) in comparison with matched controls. Remarkably, none dye/drug efflux is highly correlated with the t(8;21) chromosomal of these agents differentially affected the growth of RUNX1- translocation in pediatric acute myeloid leukemia. Leukemia 1996; 10: 1274–1282. RUNX1T1-transduced cells (Figure 2a–e). As treatment of AML 6 Schaich M, Harbich-Brutscher E, Pascheberg U, Mohr B, Soucek S, commonly involves multiple drugs, we also determined the Ehninger G et al. Association of specific cytogenetic aberrations with effect of combining two or more of these chemotherapeutic mdr1 gene expression in adult myeloid leukemia and its implication agents (using drug concentrations that resulted in 50% reduction in treatment outcome. Haematologica 2002; 87: 455–464. in cell growth as a single agent). Again, we observed little 7 Tonks A, Pearn L, Musson M, Gilkes A, Mills K, Burnett A et al. difference in the in vitro growth response of RUNX1-RUNX1T1- RUNX1-RUNXIT1 induces over-expression of gamma-catenin in human CD34(+) cells, increasing self renewal and impairing expressing cells compared to controls (Figure 2f). granulocytic differentiation. Blood 2005; 106: 841A. Taken together, these data suggest that expression of RUNX1- 8 Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, RUNX1T1 itself has no effect on the intrinsic susceptibility to Hetherington CJ et al. AML1-ETO expression is directly cytotoxic chemicals. This raises the alternative hypothesis that involved in the development of acute myeloid leukemia in the RUNX1-RUNX1T1 moderates the influence of secondary presence of additional mutations.
Recommended publications
  • Variations in Microrna-25 Expression Influence the Severity of Diabetic

    Variations in Microrna-25 Expression Influence the Severity of Diabetic

    BASIC RESEARCH www.jasn.org Variations in MicroRNA-25 Expression Influence the Severity of Diabetic Kidney Disease † † † Yunshuang Liu,* Hongzhi Li,* Jieting Liu,* Pengfei Han, Xuefeng Li, He Bai,* Chunlei Zhang,* Xuelian Sun,* Yanjie Teng,* Yufei Zhang,* Xiaohuan Yuan,* Yanhui Chu,* and Binghai Zhao* *Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Medical Research Center, Heilongjiang, People’s Republic of China; and †Clinical Laboratory of Hong Qi Hospital, Mudanjiang Medical University, Heilongjiang, People’s Republic of China ABSTRACT Diabetic nephropathy is characterized by persistent albuminuria, progressive decline in GFR, and second- ary hypertension. MicroRNAs are dysregulated in diabetic nephropathy, but identification of the specific microRNAs involved remains incomplete. Here, we show that the peripheral blood from patients with diabetes and the kidneys of animals with type 1 or 2 diabetes have low levels of microRNA-25 (miR-25) compared with those of their nondiabetic counterparts. Furthermore, treatment with high glucose decreased the expression of miR-25 in cultured kidney cells. In db/db mice, systemic administration of an miR-25 agomir repressed glomerular fibrosis and reduced high BP. Notably, knockdown of miR-25 in normal mice by systemic administration of an miR-25 antagomir resulted in increased proteinuria, extracellular matrix accumulation, podocyte foot process effacement, and hypertension with renin-angiotensin system activation. However, excessive miR-25 did not cause kidney dysfunction in wild-type mice. RNA sequencing showed the alteration of miR-25 target genes in antagomir-treated mice, including the Ras-related gene CDC42. In vitro,cotrans- fection with the miR-25 antagomir repressed luciferase activity from a reporter construct containing the CDC42 39 untranslated region.
  • ABCG1 (ABC8), the Human Homolog of the Drosophila White Gene, Is a Regulator of Macrophage Cholesterol and Phospholipid Transport

    ABCG1 (ABC8), the Human Homolog of the Drosophila White Gene, Is a Regulator of Macrophage Cholesterol and Phospholipid Transport

    ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport Jochen Klucken*, Christa Bu¨ chler*, Evelyn Orso´ *, Wolfgang E. Kaminski*, Mustafa Porsch-Ozcu¨ ¨ ru¨ mez*, Gerhard Liebisch*, Michael Kapinsky*, Wendy Diederich*, Wolfgang Drobnik*, Michael Dean†, Rando Allikmets‡, and Gerd Schmitz*§ *Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, 93042 Regensburg, Germany; †National Cancer Institute, Laboratory of Genomic Diversity, Frederick, MD 21702-1201; and ‡Departments of Ophthalmology and Pathology, Columbia University, Eye Research Addition, New York, NY 10032 Edited by Jan L. Breslow, The Rockefeller University, New York, NY, and approved November 3, 1999 (received for review June 14, 1999) Excessive uptake of atherogenic lipoproteins such as modified low- lesterol transport. Although several effector molecules have been density lipoprotein complexes by vascular macrophages leads to proposed to participate in macrophage cholesterol efflux (6, 9), foam cell formation, a critical step in atherogenesis. Cholesterol efflux including endogenous apolipoprotein E (10) and the cholesteryl mediated by high-density lipoproteins (HDL) constitutes a protective ester transfer protein (11), the detailed molecular mechanisms mechanism against macrophage lipid overloading. The molecular underlying cholesterol export in these cells have not yet been mechanisms underlying this reverse cholesterol transport process are characterized. currently not fully understood. To identify effector proteins that are Recently, mutations of the ATP-binding cassette (ABC) trans- involved in macrophage lipid uptake and release, we searched for porter ABCA1 gene have been causatively linked to familial HDL genes that are regulated during lipid influx and efflux in human deficiency and Tangier disease (12–14).
  • Ncomms6419.Pdf

    Ncomms6419.Pdf

    ARTICLE Received 6 Jun 2014 | Accepted 29 Sep 2014 | Published 7 Nov 2014 DOI: 10.1038/ncomms6419 OPEN Mechanistic determinants of the directionality and energetics of active export by a heterodimeric ABC transporter Nina Grossmann1,*, Ahmet S. Vakkasoglu2,*, Sabine Hulpke1, Rupert Abele1, Rachelle Gaudet2 & Robert Tampe´1,3 The ATP-binding cassette (ABC) transporter associated with antigen processing (TAP) participates in immune surveillance by moving proteasomal products into the endoplasmic reticulum (ER) lumen for major histocompatibility complex class I loading and cell surface presentation to cytotoxic T cells. Here we delineate the mechanistic basis for antigen translocation. Notably, TAP works as a molecular diode, translocating peptide substrates against the gradient in a strict unidirectional way. We reveal the importance of the D-loop at the dimer interface of the two nucleotide-binding domains (NBDs) in coupling substrate translocation with ATP hydrolysis and defining transport vectoriality. Substitution of the conserved aspartate, which coordinates the ATP-binding site, decreases NBD dimerization affinity and turns the unidirectional primary active pump into a passive bidirectional nucleotide-gated facilitator. Thus, ATP hydrolysis is not required for translocation per se, but is essential for both active and unidirectional transport. Our data provide detailed mechanistic insight into how heterodimeric ABC exporters operate. 1 Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Max-von-Laue-Street 9, D-60438 Frankfurt/M., Germany. 2 Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, Massachusetts 02138, USA. 3 Cluster of Excellence Frankfurt—Macromolecular Complexes, Goethe-University Frankfurt, Max-von-Laue-Street 9, D-60438 Frankfurt/M., Germany. * These authors contributed equally to this work.
  • ABCB7 Gene ATP Binding Cassette Subfamily B Member 7

    ABCB7 Gene ATP Binding Cassette Subfamily B Member 7

    ABCB7 gene ATP binding cassette subfamily B member 7 Normal Function The ABCB7 gene provides instructions for making a protein known as an ATP-binding cassette (ABC) transporter. ABC transporter proteins carry many types of molecules across membranes in cells. The ABCB7 protein is located in the inner membrane of cell structures called mitochondria. Mitochondria are involved in a wide variety of cellular activities, including energy production, chemical signaling, and regulation of cell growth and division. In the mitochondria of developing red blood cells (erythroblasts), the ABCB7 protein plays a critical role in the production of heme. Heme contains iron and is a component of hemoglobin, the protein that carries oxygen in the blood. The ABCB7 protein is also involved in the formation of certain proteins containing clusters of iron and sulfur atoms (Fe-S clusters). Researchers suspect that the ABCB7 protein transports Fe-S clusters from mitochondria, where they are formed, to the surrounding cellular fluid (cytosol), where they can be incorporated into proteins. Overall, researchers believe that the ABCB7 protein helps maintain an appropriate balance of iron (iron homeostasis) in developing red blood cells. Health Conditions Related to Genetic Changes X-linked sideroblastic anemia and ataxia At least three mutations in the ABCB7 gene have been identified in people with X-linked sideroblastic anemia with ataxia. Each of these mutations changes a single protein building block (amino acid) in the ABCB7 protein, slightly altering its structure. These changes disrupt the protein's usual role in heme production and iron homeostasis. Anemia results when heme cannot be produced normally, and therefore not enough hemoglobin is made.
  • Structures and Functions of Mitochondrial ABC Transporters

    Structures and Functions of Mitochondrial ABC Transporters

    ATP-binding cassette transporters: from mechanism to organism 943 Structures and functions of mitochondrial ABC transporters Theresia A. Schaedler*, Belinda Faust†, Chitra A. Shintre†, Elisabeth P. Carpenter†, Vasundara Srinivasan‡, Hendrik W. van Veen§ and Janneke Balk1 *Department of Biological Chemistry and Crop Protection, Rothamsted Research, West Common, Harpenden, AL5 2JQ, U.K. †Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, U.K. ‡LOEWE center for synthetic microbiology (SYNMIKRO) and Philipps University, D-35043 Marburg, Germany §Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, U.K. John Innes Centre and University of East Anglia, Colney Lane, Norwich, NR4 7UH, U.K. Abstract A small number of physiologically important ATP-binding cassette (ABC) transporters are found in mitochondria. Most are half transporters of the B group forming homodimers and their topology suggests they function as exporters. The results of mutant studies point towards involvement in iron cofactor biosynthesis. In particular, ABC subfamily B member 7 (ABCB7) and its homologues in yeast and plants are required for iron-sulfur (Fe-S) cluster biosynthesis outside of the mitochondria, whereas ABCB10 is involved in haem biosynthesis. They also play a role in preventing oxidative stress. Mutations in ABCB6 and ABCB7 have been linked to human disease. Recent crystal structures of yeast Atm1 and human ABCB10 have been key to identifying substrate-binding sites and transport mechanisms. Combined with in vitro and in vivo studies, progress is being made to find the physiological substrates of the different mitochondrial ABC transporters. Sequence analysis of mitochondrial ABC The ABCB7 group, which includes the ABC transporters transporters of the mitochondria Atm1 in yeast and ATM3 in Arabidopsis, Mitochondria of most eukaryote species harbour 2–4 can be found in virtually all eukaryotic species.
  • Genetic Basis of Sjo¨Gren's Syndrome. How Strong Is the Evidence?

    Genetic Basis of Sjo¨Gren's Syndrome. How Strong Is the Evidence?

    Clinical & Developmental Immunology, June–December 2006; 13(2–4): 209–222 Genetic basis of Sjo¨gren’s syndrome. How strong is the evidence? JUAN-MANUEL ANAYA1,2, ANGE´ LICA MARI´A DELGADO-VEGA1,2,& JOHN CASTIBLANCO1 1Cellular Biology and Immunogenetics Unit, Corporacio´n para Investigaciones Biolo´gicas, Medellı´n, Colombia, and 2Universidad del Rosario, Medellı´n, Colombia Abstract Sjo¨gren’s syndrome (SS) is a late-onset chronic autoimmune disease (AID) affecting the exocrine glands, mainly the salivary and lachrymal. Genetic studies on twins with primary SS have not been performed, and only a few case reports describing twins have been published. The prevalence of primary SS in siblings has been estimated to be 0.09% while the reported general prevalence of the disease is approximately 0.1%. The observed aggregation of AIDs in families of patients with primary SS is nevertheless supportive for a genetic component in its etiology. In the absence of chromosomal regions identified by linkage studies, research has focused on candidate gene approaches (by biological plausibility) rather than on positional approaches. Ancestral haplotype 8.1 as well as TNF, IL10 and SSA1 loci have been consistently associated with the disease although they are not specific for SS. In this review, the genetic component of SS is discussed on the basis of three known observations: (a) age at onset and sex-dependent presentation, (b) familial clustering of the disease, and (c) dissection of the genetic component. Since there is no strong evidence for a specific genetic component in SS, a large international and collaborative study would be suitable to assess the genetics of this disorder.
  • ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center

    ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center

    University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2008 ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Chemicals and Drugs Commons, and the Medical Sciences Commons Recommended Citation Fukuda, Yu , "ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters" (2008). Theses and Dissertations (ETD). Paper 345. http://dx.doi.org/10.21007/etd.cghs.2008.0100. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Interdisciplinary Program Research Advisor John D. Schuetz, Ph.D. Committee Linda Hendershot, Ph.D. James I. Morgan, Ph.D. Anjaparavanda P. Naren, Ph.D. Jie Zheng, Ph.D. DOI 10.21007/etd.cghs.2008.0100 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/345 ABCB6 IS A PORPHYRIN TRANSPORTER WITH A NOVEL TRAFFICKING SIGNAL THAT
  • Analyzing the Genes Related to Alzheimer's Disease Via a Network

    Analyzing the Genes Related to Alzheimer's Disease Via a Network

    Hu et al. Alzheimer's Research & Therapy (2017) 9:29 DOI 10.1186/s13195-017-0252-z RESEARCH Open Access Analyzing the genes related to Alzheimer’s disease via a network and pathway-based approach Yan-Shi Hu1, Juncai Xin1, Ying Hu1, Lei Zhang2* and Ju Wang1* Abstract Background: Our understanding of the molecular mechanisms underlying Alzheimer’s disease (AD) remains incomplete. Previous studies have revealed that genetic factors provide a significant contribution to the pathogenesis and development of AD. In the past years, numerous genes implicated in this disease have been identified via genetic association studies on candidate genes or at the genome-wide level. However, in many cases, the roles of these genes and their interactions in AD are still unclear. A comprehensive and systematic analysis focusing on the biological function and interactions of these genes in the context of AD will therefore provide valuable insights to understand the molecular features of the disease. Method: In this study, we collected genes potentially associated with AD by screening publications on genetic association studies deposited in PubMed. The major biological themes linked with these genes were then revealed by function and biochemical pathway enrichment analysis, and the relation between the pathways was explored by pathway crosstalk analysis. Furthermore, the network features of these AD-related genes were analyzed in the context of human interactome and an AD-specific network was inferred using the Steiner minimal tree algorithm. Results: We compiled 430 human genes reported to be associated with AD from 823 publications. Biological theme analysis indicated that the biological processes and biochemical pathways related to neurodevelopment, metabolism, cell growth and/or survival, and immunology were enriched in these genes.
  • Genome-Wide Identification of Whole ATP-Binding Cassette (ABC)

    Genome-Wide Identification of Whole ATP-Binding Cassette (ABC)

    Jeong et al. BMC Genomics 2014, 15:651 http://www.biomedcentral.com/1471-2164/15/651 RESEARCH ARTICLE Open Access Genome-wide identification of whole ATP-binding cassette (ABC) transporters in the intertidal copepod Tigriopus japonicus Chang-Bum Jeong1, Bo-Mi Kim2, Jae-Seong Lee2* and Jae-Sung Rhee3* Abstract Backgrounds: The ATP-binding cassette (ABC) transporter superfamily is one of the largest transporter gene families and is observed in all animal taxa. Although a large set of transcriptomic data was recently assembled for several species of crustaceans, identification and annotation of the large ABC transporter gene family have been very challenging. Results: In the intertidal copepod Tigriopus japonicus, 46 putative ABC transporters were identified using in silico analysis, and their full-length cDNA sequences were characterized. Phylogenetic analysis revealed that the 46 T. japonicus ABC transporters are classified into eight subfamilies (A-H) that include all the members of all ABC subfamilies, consisting of five ABCA, five ABCB, 17 ABCC, three ABCD, one ABCE, three ABCF, seven ABCG, and five ABCH subfamilies. Of them, unique isotypic expansion of two clades of ABCC1 proteins was observed. Real-time RT-PCR-based heatmap analysis revealed that most T. japonicus ABC genes showed temporal transcriptional expression during copepod development. The overall transcriptional profile demonstrated that half of all T. japonicus ABC genes were strongly associated with at least one developmental stage. Of them, transcripts TJ-ABCH_88708 and TJ-ABCE1 were highly expressed during all developmental stages. Conclusions: The whole set of T. japonicus ABC genes and their phylogenetic relationships will provide a better understanding of the comparative evolution of essential gene family resources in arthropods, including the crustacean copepods.
  • ABCD3 (F-1): Sc-514728

    ABCD3 (F-1): Sc-514728

    SANTA CRUZ BIOTECHNOLOGY, INC. ABCD3 (F-1): sc-514728 BACKGROUND APPLICATIONS The peroxisomal membrane contains several ATP-binding cassette (ABC) ABCD3 (F-1) is recommended for detection of ABCD3 of human origin by transporters, ABCD1-4 that are known to be present in the human peroxisome Western Blotting (starting dilution 1:100, dilution range 1:100-1:1000), membrane. All four proteins are ABC half-transporters, which dimerize to form immunoprecipitation [1-2 µg per 100-500 µg of total protein (1 ml of cell an active transporter. A mutation in the ABCD1 gene causes X-linked adreno- lysate)], immunofluorescence (starting dilution 1:50, dilution range 1:50- leukodystrophy (X-ALD), a peroxisomal disorder which affects lipid storage. 1:500) and solid phase ELISA (starting dilution 1:30, dilution range 1:30- ABCD2 in mouse is expressed at high levels in the brain and adrenal organs, 1:3000). which are adversely affected in X-ALD. The peroxisomal membrane comprises Suitable for use as control antibody for ABCD3 siRNA (h): sc-41147, ABCD3 two quantitatively major proteins, PMP22 and ABCD3. ABCD3 is associated shRNA Plasmid (h): sc-41147-SH and ABCD3 shRNA (h) Lentiviral Particles: with irregularly shaped vesicles which may be defective peroxisomes or per- sc-41147-V. oxisome precursors. ABCD1 localizes to peroxisomes. ABCB7 is a half-trans- porter involved in the transport of heme from the mitochondria to the cytosol. Molecular Weight of ABCD3: 75 kDa. Positive Controls: HeLa whole cell lysate: sc-2200, SH-SY5Y cell lysate: REFERENCES sc-3812 or Caco-2 cell lysate: sc-2262.
  • Three Hundred Twenty-Six Genetic Variations in Genes Encoding Nine Members of ATP-Binding Cassette, Subfamily B (ABCB/MDR/TAP), in the Japanese Population

    Three Hundred Twenty-Six Genetic Variations in Genes Encoding Nine Members of ATP-Binding Cassette, Subfamily B (ABCB/MDR/TAP), in the Japanese Population

    4600/38J Hum Genet (2002) 47:38–50 N. Matsuda et al.: © Jpn EGF Soc receptor Hum Genet and osteoblastic and Springer-Verlag differentiation 2002 ORIGINAL ARTICLE Susumu Saito · Aritoshi Iida · Akihiro Sekine Yukie Miura · Chie Ogawa · Saori Kawauchi Shoko Higuchi · Yusuke Nakamura Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population Received: September 18, 2001 / Accepted: November 2, 2001 Abstract We screened DNAs from 48 Japanese individuals domain (Hyde et al. 1990). ABC proteins constitute a super- for single-nucleotide polymorphisms (SNPs) in nine genes family consisting of eight subfamilies: ABC1, MDR/TAP, encoding components of ATP-binding cassette subfamily CFTR/MRP, ALD, OABP, GCN20, WHITE, and ANSA B (ABCB/MDR/TAP) by directly sequencing the entire (Kerb et al. 2001; Human ABC gene nomenclature applicable genomic regions except for repetitive elements. committee, http://www.gene.ucl.ac.uk/nomenclature/ This approach identified 297 SNPs and 29 insertion/deletion genefamily/abc.html). polymorphisms among the nine genes. Of the 297 SNPs, 50 Members of the MDR/TAP subfamily include the were identified in the ABCB1 gene, 14 in TAP1, 35 in ATP-binding cassette, subfamily B (ABCB) and the TAP2, 48 in ABCB4, 13 in ABCB7, 21 in ABCB8, 21 in transporter associated with antigen processing (TAP). The ABCB9, 13 in ABCB10, and 82 in ABCB11. Thirteen were ABCB1 [ATP-binding cassette, subfamily B, member 1, located in 5Ј flanking regions, 237 in introns, 37 in exons, also called multidrug resistance (MDR)-1] gene encodes P- and 10 in 3Ј flanking regions.
  • Xenopus in the Amphibian Ancestral Organization of the MHC Revealed

    Xenopus in the Amphibian Ancestral Organization of the MHC Revealed

    Ancestral Organization of the MHC Revealed in the Amphibian Xenopus Yuko Ohta, Wilfried Goetz, M. Zulfiquer Hossain, Masaru Nonaka and Martin F. Flajnik This information is current as of September 29, 2021. J Immunol 2006; 176:3674-3685; ; doi: 10.4049/jimmunol.176.6.3674 http://www.jimmunol.org/content/176/6/3674 Downloaded from References This article cites 70 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/176/6/3674.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Ancestral Organization of the MHC Revealed in the Amphibian Xenopus1 Yuko Ohta,2* Wilfried Goetz,* M. Zulfiquer Hossain,* Masaru Nonaka,† and Martin F. Flajnik* With the advent of the Xenopus tropicalis genome project, we analyzed scaffolds containing MHC genes. On eight scaffolds encompassing 3.65 Mbp, 122 MHC genes were found of which 110 genes were annotated.