DOCSLIB.ORG

NAC-1, a Potential Stem Cell Pluripotency Factor, Contributes to Paclitaxel Resistance in Ovarian Cancer Through Inactivating Gadd45 Pathway

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
NAC-1, a Potential Stem Cell Pluripotency Factor, Contributes to Paclitaxel Resistance in Ovarian Cancer Through Inactivating Gadd45 Pathway Oncogene (2009) 28, 1941–1948 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc ORIGINAL ARTICLE NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway N Jinawath1, C Vasoontara1, K-L Yap1, MM Thiaville1, K Nakayama2, T-L Wang1 andI-M Shih 1 1Departments of Pathology, Oncology, and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA and 2Department of Gynecology and Obstetrics, Shimane University, Izumo, Japan Nucleus accumbens-1 (Nac1 or NAC-1) belongs to the 22 430 new cases and15 280 deathsin 2007 (Jemal et al., BTB/POZ (Pox virus and Zinc finger/Bric-a-brac Tram- 2007). Unlike other histological types of ovarian track Broad complex) transcription factor family and is a epithelial tumors, high-grade serous carcinoma is the novel protein that potentially participates in self-renewal most aggressive andmost rapidly growing neoplasm, and pluripotency in embryonic stem cells. In human andhas a 5-year survival rate below 30%. Patients with cancer, NAC-1 is upregulated in several types of high-grade serous carcinomas always present their neoplasms, but particularly in recurrent chemoresistant diseases at the advanced stages. These patients routinely ovarian carcinomas, suggesting a biological role for NAC- receive cytoreduction surgery followed by a combined 1 in the development of drug resistance in ovarian cancer. carboplatin/paclitaxel chemotherapy regimen. Despite We have assessed this possibility and shown a correlation initial responsiveness to the chemotherapeutic drugs, between NAC-1 expression and ex vivo paclitaxel most patients eventually develop chemoresistant tumors resistance in ovarian serous carcinoma tissues and cell andsuccumb to their diseases.Therefore, treatment lines. We found that expression of Gadd45-c-interacting failure is often attributedto primary or acquired protein 1 (Gadd45gip1), a downstream target negatively resistance to chemotherapeutic agents, which remains regulated by NAC-1, was reduced in paclitaxel-resistant a clinically formidable problem in managing most cells. Ectopic expression of NAC-1 or knockdown of cancer patients. Understanding chemoresistance at the Gadd45gip1 conferred paclitaxel resistance, whereas molecular level shouldilluminate fundamental proper- NAC-1 knockdown or ectopic expression of Gadd45gip1 ties of drug resistance and provide new therapeutic increased paclitaxel sensitivity. Furthermore, silencing targets to treat advanced neoplastic diseases. NAC-1 expression or disrupting NAC-1 homodimeriza- In an effort to elucidate the molecular etiology of tion by a dominant negative NAC-1 protein that contained drug resistance, we have earlier identified and character- only the BTB/POZ domain induced the expression of izedthe nucleus accumbens-1 (Nac1 or NAC-1) as one Gadd45c, which interacted with Gadd45gip1. Reducing of the candidate chemoresistance genes in ovarian Gadd45c expression by small hairpin RNAs partially cancer (Nakayama et al., 2006a, b). NAC-1 is a nuclear enhanced paclitaxel resistance. Thus, this study provides protein belonging to the BTB/POZ (Pox virus andZinc new evidence that NAC-1 upregulation and homodimer- finger/Bric-a-brac Tramtrack Broadcomplex) domain ization contribute to tumor recurrence by equipping family. NAC-1 was originally identifiedandclonedas a ovarian cancer cells with the paclitaxel-resistant pheno- novel transcript from the NAC, a unique forebrain type through negative regulation of the Gadd45 pathway. structure involvedin rewardmotivation andaddictive Oncogene (2009) 28, 1941–1948; doi:10.1038/onc.2009.37; behaviors (Koob, 1996; Cha et al., 1997; Kalivas et al., publishedonline 23 March 2009 1999; Mackler et al., 2000), andit was later shown to be involvedin the acute behavioral andneurochemical Keywords: ovarian; NAC-1; chemoresistance; paclitaxel responses to psychomotor stimulants (Mackler et al., 2008). Recently, NAC-1 has been foundto be one of the factors associatedwith pluripotency in embryonic stem (ES) cells. NAC-1 transcriptionally regulates gene Introduction expression of other pluripotency factors, including Nanog, Oct4, Sox2, Klf4, Sall1 andSall4, andpartici- Ovarian cancer represents the most lethal gynecological pates in constituting the protein interaction and malignant disease in the United States with an estimated transcriptional regulatory networks that are critical to establish and/or maintain ES cell pluripotency (Wang Correspondence: Dr I-M Shih, Department of Pathology, Johns et al., 2006; Kim et al., 2008; Muller et al., 2008). In Hopkins Medial Institutions, CRB-II, Room 306, 1550 Orleans Street, human cancer, NAC-1 is upregulatedin several neo- Baltimore, MD 21231, USA. plasms, including ovarian high-grade serous carcinoma, E-mail: [email protected] Received14 October 2008; revised18 February 2009; accepted19 pancreatic carcinoma, colorectal carcinoma, breast February 2009; publishedonline 23 March 2009 carcinoma, renal cell carcinoma, hepatocellular carci- NAC-1 in paclitaxel resistance N Jinawath et al 1942 noma andcervical cancer (Nakayama et al., 2006a, b; a 100 OVCAR3 TR Yeasmin et al., 2008). In ovarian high-grade serous A2780 TR carcinomas, the levels of NAC-1 expression were 80 SKOV3 TR significantly higher in recurrent post-chemotherapy 60 OVCAR3 naive samples than in primary earlier untreatedtumors A2780 naive 40 SKOV3 naive (Nakayama et al., 2006a, b; Davidson et al., 2007). Furthermore, intense NAC-1 immunoreactivity Cell number 20 in primary ovarian serous carcinomas was associated (% of untreated cells) 0 with early recurrence, suggesting that NAC-1 is 0.0 0.5 2000 4000 6000 8000 10000 potentially involvedin the pathogenesis of drug Paclitaxel (nM) resistance. b At the molecular level, NAC-1 proteins form homo- OVCAR3 TR dimers through the BTB/POZ domain, and this process OVCAR3 naive is essential for tumor-cell growth andsurvival in tumors with NAC-1 overexpression (Nakayama et al., A2780 TR 2006a, b). NAC-1 has been shown to interact A2780 naive with nuclear proteins, including CoRest and histone deacetylases, HDAC3 and HDAC4, in which the SKOV3 TR binding with deacetylases is mediated by a unique SKOV3 naive BEN domain on NAC-1 protein (Korutla et al., 2005, 2007; Abhiman et al., 2008). Ectopic expression of full- 0 10 20 30 40 50 60 length NAC-1 proteins is sufficient to enhance tumor- Relative NAC-1 mRNA expression igenecity of ovarian surface epithelial cells andof Figure 1 Upregulation of NAC-1 transcript in paclitaxel-resistant NIH3T3 cells in athymic nu/nu mice. We have pre- ovarian cancer cell lines, including SKOV3, OVCAR3 and A2780. (a) Dose-dependent decrease in cell number in the presence of viously identified growth arrest and DNA-damage- paclitaxel. Paclitaxel-resistant cells (TR) are less sensitive to inducible Gadd45-g interacting protein (Gadd45gip1) paclitaxel than are the parental (naive) controls. (b) Paclitaxel- as one of the genes negatively regulatedby NAC-1, and resistant cell lines were analysedfor NAC-1 mRNA expression have shown that NAC-1 contributes to tumor growth using quantitative real-time reverse transcription PCR. NAC-1 expression levels were normalizedto the GAPDH expression level. andsurvival, at least in part, by inhibiting Gadd45gip1 NAC-1 is upregulatedin all paclitaxel-resistant cell lines. GAPDH, expression (Nakayama et al., 2007). The above findings glyceraldehyde-3-phosphate dehydrogenase; NAC-1, nucleus strongly suggest that NAC-1 is a tumor recurrence- accumbens-1. associatedgene in high-gradeovarian serous carcino- mas. In this study, by correlating NAC-1 expression and drug-resistance status, we determined that NAC-1 Table 1 Correlation of NAC-1 immunoreactivity andextreme drug resistance (EDR) status in ovarian cancer tissues causally contributes to chemoresistance for paclitaxel andcarboplatin andshowedthat the Gadd45pathway Taxol-EDR Taxol-LDR is involvedin NAC-1-mediatedchemoresistance in Positive staining 51 41 cancer cells. Negative staining 7 14 Fisher’s exact test P-value ¼ 0.05 Carbo-EDR Carbo-LDR Results Positive staining 44 48 Negative staining 9 12 Correlation of NAC-1 expression and paclitaxel Fisher’s exact test P-value ¼ 0.43 resistance in ovarian carcinoma Three ovarian cancer cell lines, SKOV3, OVCAR3 and Abbreviations: EDR, extreme drug resistance; LDR, low drug A2780, were usedto generate paclitaxel-resistant cells. resistance. Dose-dependent growth inhibition effects by paclitaxel are shown in Figure 1a. The IC50s of paclitaxel at 96 h for which the ex vivo drug-response status was available. were o0.1 nM in all the three parental naive cell lines, We showeda correlation between the intensity of NAC-1 but were more than 5000 nM in all the three paclitaxel- immunoreactivity andan extreme paclitaxel-resistance resistant cell lines. Quantitative real-time reverse tran- status (P ¼ 0.05) (Table 1). In contrast, there was no scription PCR was usedto determineNAC-1 transcript significant correlation (P ¼ 0.43) between carboplatin levels in the resistant andparental naive cells from each resistance andNAC-1 immunointensity. Therefore, we cell line. As shown in Figure 1b, NAC-1 mRNA was focusedon the mechanism underlying how NAC-1 highly expressedin paclitaxel-resistant cells as compared participates in paclitaxel resistance in ovarian cancer. with parental cells in all three different cell lines (Student’s t test P-value o0.001). To extrapolate the above findings to clinical specimens,
Load more

Recommended publications
  • View of HER2: Human Epidermal Growth Factor Receptor 2; TNBC: Triple-Negative Breast Resistance to Systemic Therapy in Patients with Breast Cancer
    Wen et al. Cancer Cell Int (2018) 18:128 https://doi.org/10.1186/s12935-018-0625-9 Cancer Cell International PRIMARY RESEARCH Open Access Sulbactam‑enhanced cytotoxicity of doxorubicin in breast cancer cells Shao‑hsuan Wen1†, Shey‑chiang Su2†, Bo‑huang Liou3, Cheng‑hao Lin1 and Kuan‑rong Lee1* Abstract Background: Multidrug resistance (MDR) is a major obstacle in breast cancer treatment. The predominant mecha‑ nism underlying MDR is an increase in the activity of adenosine triphosphate (ATP)-dependent drug efux trans‑ porters. Sulbactam, a β-lactamase inhibitor, is generally combined with β-lactam antibiotics for treating bacterial infections. However, sulbactam alone can be used to treat Acinetobacter baumannii infections because it inhibits the expression of ATP-binding cassette (ABC) transporter proteins. This is the frst study to report the efects of sulbactam on mammalian cells. Methods: We used the breast cancer cell lines as a model system to determine whether sulbactam afects cancer cells. The cell viabilities in the present of doxorubicin with or without sulbactam were measured by MTT assay. Protein identities and the changes in protein expression levels in the cells after sulbactam and doxorubicin treatment were determined using LC–MS/MS. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was used to analyze the change in mRNA expression levels of ABC transporters after treatment of doxorubicin with or without sulbactam. The efux of doxorubicin was measures by the doxorubicin efux assay. Results: MTT assay revealed that sulbactam enhanced the cytotoxicity of doxorubicin in breast cancer cells. The results of proteomics showed that ABC transporter proteins and proteins associated with the process of transcription and initiation of translation were reduced.
    [Show full text]
  • DNA Damage Activates a Spatially Distinct Late Cytoplasmic Cell-Cycle Checkpoint Network Controlled by MK2-Mediated RNA Stabilization
    DNA Damage Activates a Spatially Distinct Late Cytoplasmic Cell-Cycle Checkpoint Network Controlled by MK2-Mediated RNA Stabilization The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Reinhardt, H. Christian, Pia Hasskamp, Ingolf Schmedding, Sandra Morandell, Marcel A.T.M. van Vugt, XiaoZhe Wang, Rune Linding, et al. “DNA Damage Activates a Spatially Distinct Late Cytoplasmic Cell-Cycle Checkpoint Network Controlled by MK2-Mediated RNA Stabilization.” Molecular Cell 40, no. 1 (October 2010): 34–49.© 2010 Elsevier Inc. As Published http://dx.doi.org/10.1016/j.molcel.2010.09.018 Publisher Elsevier B.V. Version Final published version Citable link http://hdl.handle.net/1721.1/85107 Terms of Use Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. Molecular Cell Article DNA Damage Activates a Spatially Distinct Late Cytoplasmic Cell-Cycle Checkpoint Network Controlled by MK2-Mediated RNA Stabilization H. Christian Reinhardt,1,6,7,8 Pia Hasskamp,1,10,11 Ingolf Schmedding,1,10,11 Sandra Morandell,1 Marcel A.T.M. van Vugt,5 XiaoZhe Wang,9 Rune Linding,4 Shao-En Ong,2 David Weaver,9 Steven A. Carr,2 and Michael B. Yaffe1,2,3,* 1David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02132, USA 2Broad Institute of MIT and Harvard, Cambridge, MA 02132, USA 3Center for Cell Decision Processes,
    [Show full text]
  • Crystal Structure of Human Gadd45 Reveals an Active Dimer
    Protein Cell 2011, 2(10): 814–826 Protein & Cell DOI 10.1007/s13238-011-1090-6 RESEARCH ARTICLE Crystal structure of human Gadd45 reveals an active dimer 1,2,3* 1* 4 4 1 1 3 Wenzheng Zhang , Sheng Fu , Xuefeng Liu , Xuelian Zhao✉ , Wenchi Zhang✉ , Wei Peng , Congying Wu , Yuanyuan Li3, Xuemei Li1, Mark Bartlam1,2, Zong-Hao Zeng1 , Qimin Zhan4 , Zihe Rao1,2,3 1 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 2 Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China 3 Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China 4 State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China ✉ Correspondence: [email protected] (Z.-H. Zeng), [email protected] (Q. Zhan) Received August 23, 2011 Accepted September 19, 2011 ABSTRACT INTRODUCTION The human Gadd45 protein family plays critical roles in The human Gadd45 family of growth arrest and DNA DNA repair, negative growth control, genomic stability, damage-inducible proteins has three members, Gadd45α, cell cycle checkpoints and apoptosis. Here we report the -β, and -γ, grouped together on the basis of their amino acid crystal structure of human Gadd45, revealing a unique sequences and functional similarities (Vairapandi et al., 1996; dimer formed via a bundle of four parallel helices, Takekawa and Saito, 1998; Nakayama et al., 1999). The involving the most conserved residues among the genes encoding the α, β and γ isoforms of Gadd45 are Gadd45 isoforms.
    [Show full text]
  • Table 2. Significant
    Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S.
    [Show full text]
  • Open Dogan Phdthesis Final.Pdf
    The Pennsylvania State University The Graduate School Eberly College of Science ELUCIDATING BIOLOGICAL FUNCTION OF GENOMIC DNA WITH ROBUST SIGNALS OF BIOCHEMICAL ACTIVITY: INTEGRATIVE GENOME-WIDE STUDIES OF ENHANCERS A Dissertation in Biochemistry, Microbiology and Molecular Biology by Nergiz Dogan © 2014 Nergiz Dogan Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2014 ii The dissertation of Nergiz Dogan was reviewed and approved* by the following: Ross C. Hardison T. Ming Chu Professor of Biochemistry and Molecular Biology Dissertation Advisor Chair of Committee David S. Gilmour Professor of Molecular and Cell Biology Anton Nekrutenko Professor of Biochemistry and Molecular Biology Robert F. Paulson Professor of Veterinary and Biomedical Sciences Philip Reno Assistant Professor of Antropology Scott B. Selleck Professor and Head of the Department of Biochemistry and Molecular Biology *Signatures are on file in the Graduate School iii ABSTRACT Genome-wide measurements of epigenetic features such as histone modifications, occupancy by transcription factors and coactivators provide the opportunity to understand more globally how genes are regulated. While much effort is being put into integrating the marks from various combinations of features, the contribution of each feature to accuracy of enhancer prediction is not known. We began with predictions of 4,915 candidate erythroid enhancers based on genomic occupancy by TAL1, a key hematopoietic transcription factor that is strongly associated with gene induction in erythroid cells. Seventy of these DNA segments occupied by TAL1 (TAL1 OSs) were tested by transient transfections of cultured hematopoietic cells, and 56% of these were active as enhancers. Sixty-six TAL1 OSs were evaluated in transgenic mouse embryos, and 65% of these were active enhancers in various tissues.
    [Show full text]
  • Evolution of the DAN Gene Family in Vertebrates
    bioRxiv preprint doi: https://doi.org/10.1101/794404; this version posted June 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. RESEARCH ARTICLE Evolution of the DAN gene family in vertebrates Juan C. Opazo1,2,3, Federico G. Hoffmann4,5, Kattina Zavala1, Scott V. Edwards6 1Instituto de Ciencias Ambientales y Evolutivas, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile. 2David Rockefeller Center for Latin American Studies, Harvard University, Cambridge, MA 02138, USA. 3Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD). 4 Department of Biochemistry, Molecular Biology, Entomology, and Plant Pathology, Mississippi State University, Mississippi State, 39762, USA. Cite as: Opazo JC, Hoffmann FG, 5 Zavala K, Edwards SV (2020) Institute for Genomics, Biocomputing, and Biotechnology, Mississippi State Evolution of the DAN gene family in University, Mississippi State, 39762, USA. vertebrates. bioRxiv, 794404, ver. 3 peer-reviewed and recommended by 6 PCI Evolutionary Biology. doi: Department of Organismic and Evolutionary Biology, Harvard University, 10.1101/794404 Cambridge, MA 02138, USA. This article has been peer-reviewed and recommended by Peer Community in Evolutionary Biology Posted: 29 June 2020 doi: 10.24072/pci.evolbiol.100104 ABSTRACT Recommender: Kateryna Makova The DAN gene family (DAN, Differential screening-selected gene Aberrant in Neuroblastoma) is a group of genes that is expressed during development and plays fundamental roles in limb bud formation and digitation, kidney formation and morphogenesis and left-right axis specification.
    [Show full text]
  • Expression Profiling of KLF4
    Expression Profiling of KLF4 AJCR0000006 Supplemental Data Figure S1. Snapshot of enriched gene sets identified by GSEA in Klf4-null MEFs. Figure S2. Snapshot of enriched gene sets identified by GSEA in wild type MEFs. 98 Am J Cancer Res 2011;1(1):85-97 Table S1: Functional Annotation Clustering of Genes Up-Regulated in Klf4 -Null MEFs ILLUMINA_ID Gene Symbol Gene Name (Description) P -value Fold-Change Cell Cycle 8.00E-03 ILMN_1217331 Mcm6 MINICHROMOSOME MAINTENANCE DEFICIENT 6 40.36 ILMN_2723931 E2f6 E2F TRANSCRIPTION FACTOR 6 26.8 ILMN_2724570 Mapk12 MITOGEN-ACTIVATED PROTEIN KINASE 12 22.19 ILMN_1218470 Cdk2 CYCLIN-DEPENDENT KINASE 2 9.32 ILMN_1234909 Tipin TIMELESS INTERACTING PROTEIN 5.3 ILMN_1212692 Mapk13 SAPK/ERK/KINASE 4 4.96 ILMN_2666690 Cul7 CULLIN 7 2.23 ILMN_2681776 Mapk6 MITOGEN ACTIVATED PROTEIN KINASE 4 2.11 ILMN_2652909 Ddit3 DNA-DAMAGE INDUCIBLE TRANSCRIPT 3 2.07 ILMN_2742152 Gadd45a GROWTH ARREST AND DNA-DAMAGE-INDUCIBLE 45 ALPHA 1.92 ILMN_1212787 Pttg1 PITUITARY TUMOR-TRANSFORMING 1 1.8 ILMN_1216721 Cdk5 CYCLIN-DEPENDENT KINASE 5 1.78 ILMN_1227009 Gas2l1 GROWTH ARREST-SPECIFIC 2 LIKE 1 1.74 ILMN_2663009 Rassf5 RAS ASSOCIATION (RALGDS/AF-6) DOMAIN FAMILY 5 1.64 ILMN_1220454 Anapc13 ANAPHASE PROMOTING COMPLEX SUBUNIT 13 1.61 ILMN_1216213 Incenp INNER CENTROMERE PROTEIN 1.56 ILMN_1256301 Rcc2 REGULATOR OF CHROMOSOME CONDENSATION 2 1.53 Extracellular Matrix 5.80E-06 ILMN_2735184 Col18a1 PROCOLLAGEN, TYPE XVIII, ALPHA 1 51.5 ILMN_1223997 Crtap CARTILAGE ASSOCIATED PROTEIN 32.74 ILMN_2753809 Mmp3 MATRIX METALLOPEPTIDASE
    [Show full text]
  • DNA Modifications in Models of Alcohol Use Disorders
    Alcohol 60 (2017) 19e30 Contents lists available at ScienceDirect Alcohol journal homepage: http://www.alcoholjournal.org/ DNA modifications in models of alcohol use disorders * Christopher T. Tulisiak a, R. Adron Harris a, b, Igor Ponomarev a, b, a Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, 2500 Speedway, A4800, Austin, TX 78712, USA b The College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, A1900, Austin, TX 78712, USA article info abstract Article history: Chronic alcohol use and abuse result in widespread changes to gene expression, some of which Received 2 September 2016 contribute to the development of alcohol-use disorders (AUD). Gene expression is controlled, in part, by a Received in revised form group of regulatory systems often referred to as epigenetic factors, which includes, among other 3 November 2016 mechanisms, chemical marks made on the histone proteins around which genomic DNA is wound to Accepted 5 November 2016 form chromatin, and on nucleotides of the DNA itself. In particular, alcohol has been shown to perturb the epigenetic machinery, leading to changes in gene expression and cellular functions characteristic of Keywords: AUD and, ultimately, to altered behavior. DNA modifications in particular are seeing increasing research Alcohol fi Epigenetics in the context of alcohol use and abuse. To date, studies of DNA modi cations in AUD have primarily fi fi fi DNA methylation looked at global methylation pro les in human brain and blood, gene-speci c methylation pro les in DNMT animal models, methylation changes associated with prenatal ethanol exposure, and the potential DNA hydroxymethylation therapeutic abilities of DNA methyltransferase inhibitors.
    [Show full text]
  • Gadd45b Acts As Neuroprotective Effector in Global Ischemia- Induced Neuronal Death
    INTERNATIONAL NEUROUROLOGY JOURNAL INTERNATIONAL INJ pISSN 2093-4777 eISSN 2093-6931 Original Article Int Neurourol J 2019;23(Suppl 1):S11-21 NEU INTERNATIONAL RO UROLOGY JOURNAL https://doi.org/10.5213/inj.1938040.020 pISSN 2093-4777 · eISSN 2093-6931 Volume 19 | Number 2 June 2015 Volume pages 131-210 Official Journal of Korean Continence Society / Korean Society of Urological Research / The Korean Children’s Continence and Enuresis Society / The Korean Association of Urogenital Tract Infection and Inflammation einj.org Mobile Web Gadd45b Acts as Neuroprotective Effector in Global Ischemia- Induced Neuronal Death Chang Hoon Cho1,*, Hyae-Ran Byun1,*, Teresa Jover-Mengual1,2, Fabrizio Pontarelli1, Christopher Dejesus1, Ah-Rhang Cho3, R. Suzanne Zukin1, Jee-Yeon Hwang1,4 1Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA 2 Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe - Universidad de Valencia; Departamento de Fisiología, Universidad de Vale---ncia, Valencia, Spain 3Department of Beauty-Art, Seo-Jeong University, Seoul, Korea 4Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA Purpose: Transient global ischemia arising in human due to cardiac arrest causes selective, delayed neuronal death in hippo- campal CA1 and cognitive impairment. Growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) is a well- known molecule in both DNA damage-related pathogenesis and therapies. Emerging evidence suggests that Gadd45b is an anti-apoptotic factor in nonneuronal cells and is an intrinsic neuroprotective molecule in neurons. However, the mechanism of Gadd45b pathway is not fully examined in neurodegeneration associated with global ischemia.
    [Show full text]
  • Gadd45b Deficiency Promotes Premature Senescence and Skin Aging
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 19 Gadd45b deficiency promotes premature senescence and skin aging Andrew Magimaidas1, Priyanka Madireddi1, Silvia Maifrede1, Kaushiki Mukherjee1, Barbara Hoffman1,2 and Dan A. Liebermann1,2 1 Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA 2 Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA Correspondence to: Dan A. Liebermann, email: [email protected] Keywords: Gadd45b, senescence, oxidative stress, DNA damage, cell cycle arrest, Gerotarget Received: March 17, 2016 Accepted: April 12, 2016 Published: April 20, 2016 ABSTRACT The GADD45 family of proteins functions as stress sensors in response to various physiological and environmental stressors. Here we show that primary mouse embryo fibroblasts (MEFs) from Gadd45b null mice proliferate slowly, accumulate increased levels of DNA damage, and senesce prematurely. The impaired proliferation and increased senescence in Gadd45b null MEFs is partially reversed by culturing at physiological oxygen levels, indicating that Gadd45b deficiency leads to decreased ability to cope with oxidative stress. Interestingly, Gadd45b null MEFs arrest at the G2/M phase of cell cycle, in contrast to other senescent MEFs, which arrest at G1. FACS analysis of phospho-histone H3 staining showed that Gadd45b null MEFs are arrested in G2 phase rather than M phase. H2O2 and UV irradiation, known to increase oxidative stress, also triggered increased senescence in Gadd45b null MEFs compared to wild type MEFs. In vivo evidence for increased senescence in Gadd45b null mice includes the observation that embryos from Gadd45b null mice exhibit increased senescence staining compared to wild type embryos.
    [Show full text]
  • Genetic Deletion Ofgadd45b, a Regulator of Active DNA
    The Journal of Neuroscience, November 28, 2012 • 32(48):17059–17066 • 17059 Brief Communications Genetic Deletion of gadd45b, a Regulator of Active DNA Demethylation, Enhances Long-Term Memory and Synaptic Plasticity Faraz A. Sultan,1 Jing Wang,1 Jennifer Tront,2 Dan A. Liebermann,2 and J. David Sweatt1 1Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294 and 2Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania 19140 Dynamic epigenetic mechanisms including histone and DNA modifications regulate animal behavior and memory. While numerous enzymes regulating these mechanisms have been linked to memory formation, the regulation of active DNA demethylation (i.e., cytosine-5 demethylation) has only recently been investigated. New discoveries aim toward the Growth arrest and DNA damage- inducible 45 (Gadd45) family, particularly Gadd45b, in activity-dependent demethylation in the adult CNS. This study found memory- associated expression of gadd45b in the hippocampus and characterized the behavioral phenotype of gadd45b Ϫ/Ϫ mice. Results indicate normal baseline behaviors and initial learning but enhanced persisting memory in mutants in tasks of motor performance, aversive conditioning and spatial navigation. Furthermore, we showed facilitation of hippocampal long-term potentiation in mutants. These results implicate Gadd45b as a learning-induced gene and a regulator of memory formation and are consistent with its potential role in active DNA demethylation in memory. Introduction along with the finding of activity-induced gadd45b in the hip- Alterations in neuronal gene expression play a necessary role pocampus led us to hypothesize that Gadd45b modulates mem- in memory consolidation (Miyashita et al., 2008).
    [Show full text]
  • Gadd45a Regulates B-Catenin Distribution and Maintains Cell–Cell Adhesion/ Contact
    Oncogene (2007) 26, 6396–6405 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc ORIGINAL ARTICLE Gadd45a regulates b-catenin distribution and maintains cell–cell adhesion/ contact JJi1, R Liu1, T Tong, Y Song, S Jin, M Wu and Q Zhan State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China Gadd45a,a growth arrest and DNA-damage gene,plays 1999;Jin et al., 2000;Tong et al., 2005). Gadd45a important roles in the control of cell cycle checkpoints, also plays roles in negative regulation of cell malig- DNA repair and apoptosis. We show here that Gadd45a is nancy. Mouse embryonic fibroblasts (MEFs) derived involved in the control of cell contact inhibition and cell– from Gadd45a-null mice exhibited genomic instability, cell adhesion. Gadd45a can serve as an adapter to enhance single oncogene-mediated transformation, loss of nor- the interaction between b-catenin and Caveolin-1,and in mal cellular senescence, increased cellular proliferation, turn induces b-catenin translocation to cell membrane for centrosome amplification and reduced DNA repair maintaining cell–cell adhesion/contact inhibition. This is (Hollander et al., 1999;Smith et al., 2000). Gadd45a- coupled with reduction of b-catenin in cytoplasm and null mice have an increased frequency of tumorigenesis nucleus following Gadd45a induction,which is reflected by by ionizing radiation (IR), ultraviolet radiation (UVR) the downregulation of cyclin D1,one of the b-catenin and dimethylbenzanthracene (DMBA), although these targeted genes. Additionally,Gadd45a facilitates ultra- mice do not develop spontaneous tumors (Hollander violet radiation-induced degradation of cytoplasmic and et al., 1999, 2001;Hildesheim et al., 2002).
    [Show full text]