DOCSLIB.ORG

Regulation of the Oxidative Stress Response by Arid1a

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Regulation of the Oxidative Stress Response by Arid1a The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2015 REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A Suet Yan Kwan Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Oncology Commons Recommended Citation Kwan, Suet Yan, "REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A" (2015). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 608. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/608 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A By Suet Yan Kwan, BSc APPROVED: ______________________________ Kwong-Kwok Wong, Ph.D. Advisory Professor ______________________________ Russell Broaddus, M.D., Ph.D. ______________________________ Joya Chandra, Ph.D. ______________________________ Samuel Mok, Ph.D. ______________________________ Anil Sood, M.D. APPROVED: ____________________________ Dean, The University of Texas Graduate School of Biomedical Sciences at Houston REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A A DISSERTATION Presented to the Faculty of The University of Texas Health Science Center at Houston and The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Suet Yan Kwan, BSc Houston, Texas December, 2015 DEDICATION This thesis is dedicated to my family; mum, dad, Suet Ying, and Rita Urlanda. To Welles Chan, who has remained supportive this whole time. I wouldn’t be able to complete this thesis without him. To my best friend Danny Mak and his family, Mr. and Mrs. Mak, Andy, and Ruby Marasigan, who sadly passed away in 2014. Last but not least, this thesis is also dedicated to my dearest friend Lily Lai. In loving memory of Timothy Chan and Ruby Marasigan. iii ACKNOWLEDGMENTS First of all, I would like to thank Dr. Gershenson and the Molbeck Ovarian Clear Cell Carcinoma Fund for contributing to a part of the funding and made this research possible. I would like to thank Welles Chan. Without him, I would not have been able to complete this thesis. He was always there for me regardless if it was a good or bad day in the lab. He always listened and encouraged me. I would like to thank my advisor Dr. Kwong-Kwok Wong. He accepted me into the GSBS and allowed me to have the freedom to pursue any projects that I came up with. I would like to thank my thesis committee members Dr. Hui-Kuan Lin, Dr. Joya Chandra, Dr. Anil Sood, Dr. Russell Broaddus, and Dr. Samuel Mok for their time and advice in helping to complete this thesis. Dr. Hui-Kuan Lin is truly inspirational and has a huge breath of knowledge. He let me rotate in his lab during my first year, and served in my committee for my whole PhD until his departure from MD Anderson. I would like to thank Dr. Joya Chandra for willing to replace Dr. Hui-Kuan Lin during the final stages of my PhD. She is the expert in studying oxidative stress, and I thank her for giving me advice and her generosity in sharing her lab’s reagents. I would like to thank Dr. Anil Sood for his collaboration on the siRNA screen using ovarian cancer cells and his expertise in studying ovarian cancer. I would like to thank Dr. Russell Broaddus for his advice on how to present the background and results of my research effectively, and having high expectations of me. I would like to thank Dr. Samuel Mok for collaboration with his lab in general and his generosity in sharing his reagents. I would like to thank the current and past members of my lab. Daisy Izaguirre was very supportive both inside and outside of the lab. Yvonne Tsang Lee helped order reagents and maintained the lab. ZhiFei Zu was always friendly and helped generated lentiviruses. In collaborating labs, I would like to thank my sister Suet Ying Kwan for her expertise in analyzing the TCGA data and using the correct statistics. I would like to thank Jean Cheng for her expertise in bioinformatics and analyzing the GDSC database. I would also like to thank Chloe Co for giving me advice and technical support during the early days of my PhD. I would also like to thank members of Mok lab for giving me advice and sharing reagents with me. I would like to thank Leslie Grasse from Dr. Joya Chandra’s lab for teaching me how to do the DCFDA assay. I would also like to thank the North Campus Flow Cytometry Core Facility for their help in doing flow cytometry analyses, especially Duncan Mak who was patient in helping me whenever problems or questions came up. Finally, I would like to thank Dr. Bill Mattox from the GSBS for his advice on how to proceed successfully during the final stages of my PhD. iv ABSTRACT Regulation of the oxidative stress response by ARID1A Suet Yan Kwan, BSc Advisory Professor: Kwong-Kwok Wong, Ph.D. SWI/SNF is mutated in about 20% of all human cancers; in particular ARID1A is the most frequently mutated SWI/SNF subunit. ARID1A is a tumor suppressor gene, inactivating mutations in ARID1A are most frequently found in ovarian and endometrial cancers, specifically uterine corpus endometrioid carcinomas (UCEC), ovarian clear cell carcinomas (OCCC) and ovarian endometrioid carcinomas (OEC). The functional roles of ARID1A are not completely understood and there are limited therapeutic strategies that specifically target ARID1A-mutant cancers. Given that ARID1A expression is lost in cancer, ARID1A mutations cannot be targeted directly and novel therapeutic strategies are required to target ARID1A-mutant cancers. In this study, drug responses between ARID1A-wildtype and ARID1A-mutant cell lines were compared using the ‘Genomics of Drug Sensitivities in Cancer’ database. From this analysis, I found that ARID1A-mutant cell lines are more sensitive to elesclomol, which is a reactive oxygen species (ROS)-inducing agent. This finding was validated using a panel of ovarian and endometrial cancer cell lines, where ARID1A-mutant cell lines exhibited lower IC50 values and higher apoptotic rates when treated with elesclomol. Knockdown and re-expression of ARID1A in ovarian cancer cells showed that ARID1A is required to protect cancer cells from v oxidative stress. In the absence of ARID1A, intracellular ROS levels were increased, and this increase was required for increased cell growth upon ARID1A depletion. Next, I investigated the relationship between ARID1A and NRF2, the major regulator of the antioxidant response in the cell. I found that ARID1A negatively regulates the expression of NRF2. Knockdown of NRF2 in ovarian cancer cell lines revealed that NRF2 expression may be preferentially required for protection from oxidative stress and cell proliferation in ARID1A- mutant cells. Analysis using The Cancer Genome Atlas (TCGA) UCEC dataset revealed that ARID1A-mutant tumor samples have higher expression of NRF2 and NRF2-target genes. In summary, this study revealed novel roles of ARID1A in protecting ovarian cancer cells against oxidative stress. In the absence of ARID1A, NRF2 is up-regulated and may be required to compensate for ARID1A deficiency. These findings suggest that ROS-inducing agents and NRF2 inhibitors may be used as therapeutic strategies in targeting ARID1A-mutant ovarian cancer cells. vi TABLE OF CONTENTS DEDICATION............................................................................................................................. iii ACKNOWLEDGMENTS .......................................................................................................... iv ABSTRACT .................................................................................................................................. v TABLE OF CONTENTS .......................................................................................................... vii LIST OF FIGURES .................................................................................................................... xi LIST OF TABLES .................................................................................................................... xiii CHAPTER 1: INTRODUCTION ............................................................................................... 1 1.1 Ovarian cancer ...................................................................................................................... 1 1.2 Endometriosis-associated ovarian cancers ....................................................................... 2 1.2 The chromatin remodeler SWI/SNF..................................................................................... 3 1.2.1 Chromatin remodeling-independent functions of SWI/SNF ......................................... 4 1.2.2 Alterations of the SWI/SNF complex in cancer ............................................................ 5 1.3 Tumor suppressive
Load more

Recommended publications
  • ATF4 Promotes Angiogenesis and Neuronal Cell Death and Confers Ferroptosis in a Xct-Dependent Manner
    OPEN Oncogene (2017) 36, 5593–5608 www.nature.com/onc ORIGINAL ARTICLE ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner D Chen1,2,ZFan1,3, M Rauh4, M Buchfelder5, IY Eyupoglu1,5 and N Savaskan1,5,6 Activating transcription factor 4 (ATF4) is a critical mediator of metabolic and oxidative homeostasis and cell survival. ATF4 is elevated in response to diverse microenvironmental stresses, including starvation, ER stress damages and exposure to toxic factors. Here we show that ATF4 expression fosters the malignancy of primary brain tumors (WHO grade III and IV gliomas) and increases proliferation and tumor angiogenesis. Hence, ATF4 expression promotes cell migration and anchorage-independent cell growth, whereas siRNA-mediated knockdown of ATF4 attenuates these features of malignancy in human gliomas. Further experiments revealed that ATF4-dependent tumor promoting effects are mediated by transcriptional targeting the glutamate antiporter xCT/SCL7A11 (also known as system Xc-). Thus, xCT is elevated as a consequence of ATF4 activation. We further found evidence that ATF4-induced proliferation can be attenuated by pharmacological or genetic xCT inhibition and ferroptosis inducers such as sorafenib, erastin and GPx4 inhibitor RSL3. Further, fostered xCT expression promotes cell survival and growth in ATF4 knockdown cells. Moreover, increased xCT levels ameliorate sorafenib and erastin-induced ferroptosis. Conversely, ATF4 knockdown renders cells susceptible for erastin, sorafenib and RSL3-induced ferroptosis. We further identified that ATF4 promotes tumor-mediated neuronal cell death which can be alleviated by xCT inhibition. Moreover, elevated ATF4 expression in gliomas promotes tumor angiogenesis. Noteworthy, ATF4-induced angiogenesis could be diminished by ferroptosis inducers erastin and by GPx4 inhibitor RSL3.
    [Show full text]
  • Thesis Was Carried out at the K
    Experimental modeling and novel therapeutic strategies in melanoma brain metastasis Terje Sundstrøm Dissertation for the degree of philosophiae doctor (PhD) University of Bergen, Norway 2015 Dissertation date: June 9th 2015 LIST OF ABBREVIATIONS 3D 3-dimensional 5-ALA 5-aminolevulinic acid AAAS American Association for the Advancement of Science ACT Adoptive cell transfer ADC Apparent diffusion coefficient AJCC American Joint Committee on Cancer AKT Protein kinase B ALK Anaplastic lymphoma kinase APC Antigen-presenting cell APOE Apolipoprotein-E ATP Adenosine triphosphate B7-H3 B7 homolog 3 BBB Blood-brain barrier BCL2A1 Bcl-2-related protein A1 bFGF Basic fibroblast growth factor BLI Bioluminescence imaging BRAF Serine/threonine-protein kinase B-raf BRMS1 Breast cancer metastasis-suppressor 1 BTB Blood-tumor barrier CI (Mitochondrial) Complex I CC22 Chemokine (C-C motif) ligand 22 CD44v6 CD44 splicing variant 6 CDK4 Cyclin-dependent kinase 4 CDKN2A p16INK4A inhibitor of CDK4 cMAP Connectivity Map CNS Central nervous system COT Serine/threonine kinase Cot CRAF RAF proto-oncogene serine/threonine-protein kinase CT Computed tomography CTLA4 Cytotoxic T-lymphocyte-associated protein 4 CXCR4 C-X-C chemokine receptor type 4 2 Da Dalton (unit) DNA Deoxyribonucleic acid DWI Diffusion weighted imaging ECM Extracranial metastases EDNRB Endothelin receptor B EFSA European Foods Safety Authority EGFR Epidermal growth factor receptor ER Estrogen receptor ERBB2 Receptor tyrosine-protein kinase erbB-2 ERK Extracellular signal-regulated kinase ET3 Endothelin-3
    [Show full text]
  • Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer
    Author Manuscript Published OnlineFirst on November 21, 2016; DOI: 10.1158/0008-5472.CAN-16-1901 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Systematic drug screening identifies tractable targeted combination therapies in triple-negative breast cancer Vikram B Wali1,3, Casey G Langdon2, Matthew A Held2, James T Platt1, Gauri A Patwardhan1, Anton Safonov1, Bilge Aktas1, Lajos Pusztai1,3, David F Stern2,3,Christos Hatzis1,3 1 Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut, USA 2 Department of Pathology, Yale School of Medicine, Yale University, New Haven, Connecticut, USA 3 Yale Cancer Center, New Haven Connecticut, USA Corresponding authors: Christos Hatzis, Ph.D. or Vikram B Wali, Ph.D. Section of Medical Oncology Yale School of Medicine Yale University 333 Cedar Street PO Box 208032 New Haven, CT 06520 [email protected] [email protected] Running Title: Novel Combination Therapies in Triple Negative Breast Cancer CONFLICTS OF INTEREST Authors have no conflict of interest to disclose. 1 Downloaded from cancerres.aacrjournals.org on October 6, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 21, 2016; DOI: 10.1158/0008-5472.CAN-16-1901 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation.
    [Show full text]
  • Mitochondrial Reprogramming in Tumor Progression and Therapy M
    Published OnlineFirst December 9, 2015; DOI: 10.1158/1078-0432.CCR-15-0460 Molecular Pathways Clinical Cancer Research Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy M. Cecilia Caino and Dario C. Altieri Abstract Small-molecule inhibitors of the phosphoinositide 3-kinase mitochondrial Hsp90s in preclinical development (gamitrinib) (PI3K), Akt, and mTOR pathway currently in the clinic produce a prevents adaptive mitochondrial reprogramming and shows paradoxical reactivation of the pathway they are intended to potent antitumor activity in vitro and in vivo. Other therapeutic suppress. Furthermore, fresh experimental evidence with PI3K strategies to target mitochondria for cancer therapy include antagonists in melanoma, glioblastoma, and prostate cancer small-molecule inhibitors of mutant isocitrate dehydrogenase shows that mitochondrial metabolism drives an elaborate process (IDH) IDH1 (AG-120) and IDH2 (AG-221), which opened new of tumor adaptation culminating with drug resistance and met- therapeutic prospects for patients with high-risk acute myelog- astatic competency. This is centered on reprogramming of mito- enous leukemia (AML). A second approach of mitochondrial chondrial functions to promote improved cell survival and to fuel therapeutics focuses on agents that elevate toxic ROS levels from the machinery of cell motility and invasion. Key players in these a leaky electron transport chain; nevertheless, the clinical expe- responses are molecular chaperones of the Hsp90 family com- rience with these compounds, including a quinone derivative, partmentalized in mitochondria, which suppress apoptosis via ARQ 501, and a copper chelator, elesclomol (STA-4783) is phosphorylation of the pore component, Cyclophilin D, and limited. In light of this evidence, we discuss how best to target enable the subcellular repositioning of active mitochondria to a resurgence of mitochondrial bioenergetics for cancer therapy.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix
    United States International Trade Commission Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix USITC Publication 4208 December 2010 U.S. International Trade Commission COMMISSIONERS Deanna Tanner Okun, Chairman Irving A. Williamson, Vice Chairman Charlotte R. Lane Daniel R. Pearson Shara L. Aranoff Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix Publication 4208 December 2010 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 15, 2010, set forth at the end of this publication, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the United States International Trade Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement changes to the Pharmaceutical Appendix, effective on January 1, 2011. Table 1 International Nonproprietary Name (INN) products proposed for addition to the Pharmaceutical Appendix to the Harmonized Tariff Schedule INN CAS Number Abagovomab 792921-10-9 Aclidinium Bromide 320345-99-1 Aderbasib 791828-58-5 Adipiplon 840486-93-3 Adoprazine 222551-17-9 Afimoxifene 68392-35-8 Aflibercept 862111-32-8 Agatolimod
    [Show full text]
  • Gene Regulatory Network Analysis with Drug Sensitivity Reveals Synergistic
    www.nature.com/scientificreports OPEN Gene regulatory network analysis with drug sensitivity reveals synergistic efects of combinatory chemotherapy in gastric cancer Jeong Hoon Lee1, Yu Rang Park 2, Minsun Jung 3 & Sun Gyo Lim 4* The combination of docetaxel, cisplatin, and fuorouracil (DCF) is highly synergistic in advanced gastric cancer. We aimed to explain these synergistic efects at the molecular level. Thus, we constructed a weighted correlation network using the diferentially expressed genes between Stage I and IV gastric cancer based on The Cancer Genome Atlas (TCGA), and three modules were derived. Next, we investigated the correlation between the eigengene of the expression of the gene network modules and the chemotherapeutic drug response to DCF from the Genomics of Drug Sensitivity in Cancer (GDSC) database. The three modules were associated with functions related to cell migration, angiogenesis, and the immune response. The eigengenes of the three modules had a high correlation with DCF (−0.41, −0.40, and −0.15). The eigengenes of the three modules tended to increase as the stage increased. Advanced gastric cancer was afected by the interaction the among modules with three functions, namely cell migration, angiogenesis, and the immune response, all of which are related to metastasis. The weighted correlation network analysis model proved the complementary efects of DCF at the molecular level and thus, could be used as a unique methodology to determine the optimal combination of chemotherapy drugs for patients with gastric cancer. Although its incidence is decreasing in some parts of the world, gastric cancer is still the fourth most common cancer worldwide1,2.
    [Show full text]
  • ROS and the DNA Damage Response in Cancer T Upadhyayula Sai Srinivasa,1, Bryce W.Q
    Redox Biology 25 (2019) 101084 Contents lists available at ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox ROS and the DNA damage response in cancer T Upadhyayula Sai Srinivasa,1, Bryce W.Q. Tana,1, Balamurugan A. Vellayappanb, ⁎ Anand D. Jeyasekharana,c, a Cancer Science Institute of Singapore, National University of Singapore, Singapore b Department of Radiation Oncology, National University Hospital, Singapore c Department of Haematology-Oncology, National University Hospital, Singapore ARTICLE INFO ABSTRACT Keywords: Reactive oxygen species (ROS) are a group of short-lived, highly reactive, oxygen-containing molecules that can Reactive Oxygen Species induce DNA damage and affect the DNA damage response (DDR). There is unequivocal pre-clinical and clinical ROS evidence that ROS influence the genotoxic stress caused by chemotherapeutics agents and ionizing radiation. DNA damage response Recent studies have provided mechanistic insight into how ROS can also influence the cellular response to DNA DDR damage caused by genotoxic therapy, especially in the context of Double Strand Breaks (DSBs). This has led to Chemotherapy the clinical evaluation of agents modulating ROS in combination with genotoxic therapy for cancer, with mixed Radiotherapy success so far. These studies point to context dependent outcomes with ROS modulator combinations with Chemotherapy and radiotherapy, indicating a need for additional pre-clinical research in the field. In this review, we discuss the current knowledge on the effect of ROS in the DNA damage response, and its clinical relevance. 1. Introduction to the DNA damage response and ROS collectively termed as the DNA damage response (DDR) is activated. This response includes DNA damage recognition, activation of check- 1.1.
    [Show full text]
  • Decreased Expression of the Id3gene at 1P36.1 in Ovarian
    British Journal of Cancer (2001) 84(3), 352–359 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2000.1620, available online at http://www.idealibrary.com on http://www.bjcancer.com Decreased expression of the Id3 gene at 1p36.1 in ovarian adenocarcinomas JM Arnold1, SC Mok2, D Purdie1 and G Chenevix-Trench1,3 1The Queensland Institute of Medical Research, PO Box Royal Brisbane Hospital, Herston, Queensland, Australia, 4029; 2Laboratory of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproduction Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; 3Department of Pathology, University of Queensland, St Lucia, Brisbane, Australia, 4067 Summary The molecular events that drive the initiation and progression of ovarian adenocarcinoma are not well defined. We have investigated changes in gene expression in ovarian cancer cell lines compared to an immortalized human ovarian surface epithelial cell line (HOSE) using a cDNA array. We identified 17 genes that were under-expressed and 10 genes that were over-expressed in the cell lines compared to the HOSE cells. One of the genes under-expressed in the ovarian cancer cell lines, Id3, a transcriptional inactivator, was selected for further investigation. Id3 mRNA was expressed at reduced levels in 6 out of 9 ovarian cancer cell lines compared to the HOSE cells while at the protein level, all 7 ovarian cancer cell lines examined expressed the Id3 protein at greatly reduced levels. Expression of Id3 mRNA was also examined in primary ovarian tumours and was found in only 12/38 (32%) cases. A search was conducted for mutations of Id3 in primary ovarian cancers using single stranded conformation polymorphism (SSCP) analysis.
    [Show full text]
  • A KDM6 Inhibitor Potently Induces ATF4 and Its Target Gene Expression Through HRI Activation and by UTX Inhibition
    www.nature.com/scientificreports OPEN A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition Shojiro Kitajima1,2,8, Wendi Sun1,8, Kian Leong Lee1,3,8, Jolene Caifeng Ho1, Seiichi Oyadomari4, Takashi Okamoto5, Hisao Masai6, Lorenz Poellinger1,7,9 & Hiroyuki Kato1,5,6* UTX/KDM6A encodes a major histone H3 lysine 27 (H3K27) demethylase, and is frequently mutated in various types of human cancers. Although UTX appears to play a crucial role in oncogenesis, the mechanisms involved are still largely unknown. Here we show that a specifc pharmacological inhibitor of H3K27 demethylases, GSK-J4, induces the expression of transcription activating factor 4 (ATF4) protein as well as the ATF4 target genes (e.g. PCK2, CHOP, REDD1, CHAC1 and TRIB3). ATF4 induction by GSK-J4 was due to neither transcriptional nor post-translational regulation. In support of this view, the ATF4 induction was almost exclusively dependent on the heme-regulated eIF2α kinase (HRI) in mouse embryonic fbroblasts (MEFs). Gene expression profles with UTX disruption by CRISPR-Cas9 editing and the following stable re-expression of UTX showed that UTX specifcally suppresses the expression of the ATF4 target genes, suggesting that UTX inhibition is at least partially responsible for the ATF4 induction. Apoptosis induction by GSK-J4 was partially and cell-type specifcally correlated with the activation of ATF4-CHOP. These fndings highlight that the anti-cancer drug candidate GSK-J4 strongly induces ATF4 and its target genes via HRI activation and raise a possibility that UTX might modulate cancer formation by regulating the HRI-ATF4 axis.
    [Show full text]
  • Combinatorial Bzip Dimers Display Complex DNA-Binding Specificity Landscapes
    Combinatorial bZIP dimers display complex DNA-binding specificity landscapes The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Rodriguez-Martinez, Jose A et al. “Combinatorial bZIP Dimers Display Complex DNA-Binding Specificity Landscapes.” eLife 6 (2017): n. pag. As Published http://dx.doi.org/10.7554/eLife.19272 Publisher eLife Sciences Publications, Ltd. Version Final published version Citable link http://hdl.handle.net/1721.1/110147 Terms of Use Creative Commons Attribution 4.0 International License Detailed Terms http://creativecommons.org/licenses/by-nc/4.0/ RESEARCH ARTICLE Combinatorial bZIP dimers display complex DNA-binding specificity landscapes Jose´ A Rodrı´guez-Martı´nez1†, Aaron W Reinke2†, Devesh Bhimsaria1,3†, Amy E Keating2,4, Aseem Z Ansari1,5* 1Department of Biochemistry, University of Wisconsin-Madison, Madison, United States; 2Department of Biology, Massachusetts Institute of Technology, Cambridge, United States; 3Department of Electrical and Computer Engineering, University of Wisconsin-Madison, Madison, Unites States; 4Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States; 5The Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, United States Abstract How transcription factor dimerization impacts DNA-binding specificity is poorly understood. Guided by protein dimerization properties, we examined DNA binding specificities of 270 human bZIP pairs. DNA interactomes of 80 heterodimers and 22 homodimers revealed that 72% of heterodimer motifs correspond to conjoined half-sites preferred by partnering monomers. Remarkably, the remaining motifs are composed of variably-spaced half-sites (12%) or ‘emergent’ sites (16%) that cannot be readily inferred from half-site preferences of partnering monomers.
    [Show full text]
  • Distinct Roles of Jun : Fos and Jun : ATF Dimers in Oncogenesis
    Oncogene (2001) 20, 2453 ± 2464 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis Hans van Dam*,1 and Marc Castellazzi2 1Department of Molecular Cell Biology, Leiden University Medical Center, Sylvius Laboratories, PO Box 9503, 2300 RA Leiden, The Netherlands; 2Unite de Virologie Humaine, Institut National de la Sante et de la Recherche MeÂdicale (INSERM-U412), Ecole Normale SupeÂrieure, 46 alleÂe d'Italie, 69364 Lyon Cedex 07, France Jun : Fos and Jun : ATF complexes represent two classes dimers with emphasis on their roles in oncogenic of AP-1 dimers that (1) preferentially bind to either transformation in avian model systems. Previous heptameric or octameric AP-1 binding sites, and (2) are reviews on AP-1 and cell transformation include dierently regulated by cellular signaling pathways and references: (Angel and Karin, 1991; Wisdom, 1999; oncogene products. To discriminate between the func- Vogt, 1994; Karin et al., 1997; van Dam and van der tions of Jun : Fos, Jun: ATF and Jun : Jun, mutants were Eb, 1994; Hagmeyer et al., 1995). developed that restrict the ability of Jun to dimerize either to itself, or to Fos(-like) or ATF(-like) partners. Introduction of these mutants in chicken embryo Jun : Fos and Jun : ATF transcription factors: dimeric ®broblasts shows that Jun : Fra2 and Jun : ATF2 dimers complexes with variable composition and activities play distinct, complementary roles in in vitro oncogenesis by inducing either anchorage independence or growth AP-1 sub-units: members of the bZip protein family factor independence, respectively.
    [Show full text]
  • ARID1A Protein Expression Is Retained in Ovarian Endometriosis
    www.nature.com/scientificreports OPEN ARID1A protein expression is retained in ovarian endometriosis with ARID1A loss‑of‑function mutations: implication for the two‑hit hypothesis Nozomi Yachida1, Kosuke Yoshihara1*, Kazuaki Suda1, Hirofumi Nakaoka2,3, Haruka Ueda1, Kentaro Sugino1, Manako Yamaguchi1, Yutaro Mori1, Kaoru Yamawaki1, Ryo Tamura1, Tatsuya Ishiguro1, Masanori Isobe1, Teiichi Motoyama4, Ituro Inoue2 & Takayuki Enomoto1 ARID1A loss‑of‑function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis‑associated ovarian cancer. Although our recent genomic study clarifed that ARID1A loss‑of‑function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss‑of‑function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss‑of‑function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss‑of‑ function mutations or both a single ARID1A loss‑of‑function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss‑of‑function mutations. These results suggest that a single ARID1A loss‑of‑function mutation is insufcient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss‑of‑function mutations.
    [Show full text]