DOCSLIB.ORG

RGS12 Is a Novel Tumor Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
RGS12 Is a Novel Tumor Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression Author Manuscript Published OnlineFirst on June 13, 2017; DOI: 10.1158/0008-5472.CAN-17-0669 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RGS12 is a novel tumor suppressor gene in African American prostate cancer that represses AKT and MNX1 expression Yongquan Wang*1,2, Jianghua Wang* 2, Li Zhang2,3, Omer Faruk Karatas#2, Longjiang Shao2 , Yiqun Zhang4, Patricia Castro2, Chad J. Creighton4,5 and Michael Ittmann2 1Department of Urology, Southwest Hospital, Third Military Medical University Chongqing, China; 2Dept. of Pathology & Immunology, Baylor College of Medicine and Michael E. DeBakey Dept. of Veterans Affairs Medical Center; 3Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China; 4Dan L. Duncan Cancer Comprehensive Cancer Center Division of Biostatistics; 5Department of Medicine, Baylor College of Medicine, Houston, Texas 77030 *These authors contributed equally to this project as co-first authors # Current address: Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey. Running title: RGS12 in African American prostate cancer Keywords: prostate cancer, RGS12, MNX1, AKT, African American Financial support: This work was supported grants from the Department of Defense Prostate Cancer Research Program (W81XWH-12-1-0046 MI); the National Cancer Institute supporting the Dan L. Duncan Cancer Center (P30 CA125123) Human Tissue Acquisition and Pathology and Genomic and RNA Profiling Shared Resources; the Prostate Cancer Foundation (MI) and by the use of the facilities of the Michael E. DeBakey VAMC. Conflicts of interest: The authors declare no potential conflicts of interest Word count: 4484 Figures: 7 Correspondence: Michael Ittmann MD/PhD Department of Pathology and Immunology Baylor College of Medicine One Baylor Plaza Houston, TX 77030 Tele: (713) 798-6196 Fax: (713) 798-5838 E-mail: [email protected] 1 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 13, 2017; DOI: 10.1158/0008-5472.CAN-17-0669 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT African American (AA) men exhibit a relatively high incidence and mortality due to prostate cancer (PCa) even after adjustment for socioeconomic factors, but the biological basis for this disparity is unclear. Here we identify a novel region on chromosome 4p16.3 that is lost selectively in AA PCa. The negative regulator of G-protein signaling RGS12 was defined as the target of 4p16.3 deletions, although it has not been implicated previously as a tumor suppressor gene. RGS12 transcript levels were relatively reduced in AA PCa and PCa cell lines showed decreased RGS12 expression relative to benign prostate epithelial cells. Notably, RGS12 exhibited potent tumor suppressor activity in PCa and prostate epithelial cell lines in vitro and in vivo. We found that RGS12 expression correlated negatively with the oncogene MNX1 and regulated its expression in vitro and in vivo. Further, MNX1 was regulated by AKT activity and RGS12 expression decreased total and activated AKT levels. Our findings identify RGS12 is a candidate tumor suppressor gene in AA PCa which acts by decreasing expression of AKT and MNX1, establishing a novel oncogenic axis in this disparate disease setting. 2 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 13, 2017; DOI: 10.1158/0008-5472.CAN-17-0669 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION African American (AA) men have a significantly higher incidence of prostate cancer (PCa) compared to European American (EA) men(1) and are twice as likely to die from PCa compared to EA men. The biological basis for this difference in PCa mortality is unclear. Since AA men account for a significant fraction of all PCa related deaths in in the US, it is important to understand the basis for this higher mortality in order to optimize prevention and treatment strategies for this higher risk group of men. There have been a number of studies comparing PCa tissues from AA and EA men. Several studies have compared gene expression in AA and EA PCa using large scale expression microarrays (2-5) including a study from our group (6). A number of studies have focused on a smaller set of preselected genes (7-9). All of these studies indicate that there is differential gene expression between AA and EA PCa. The TMPRSS2/ERG fusion gene is much less frequent in AA PCa based on studies of DNA, RNA and protein (8-16). Elevated SPINK1 expression appears to be more common in AA PCa (8,9,17-19). Among other genes upregulated in AA PCa, inflammatory genes are prominent (2,4,7). We have recently identified MNX1 as an oncogene that is expressed at significantly higher levels in AA PCa compared to EA PCa (6). We further demonstrated that MNX1 is regulated by AKT and androgen receptor activity and upregulates lipid synthesis, which has been linked to aggressive disease (20,21) and thus MNX1 may contribute to disease aggressiveness in AA PCa. We have published (22) a study of allelic loss and gain in 20 AA PCas using Affymetrix 500k SNP arrays to define regions of recurrent copy number gain and loss in localized PCa and compared the pattern of copy number alterations (CNAs) to that of a similar cohort of EA men (23). We found multiple cytobands with a statistically higher frequency of CNAs in our AA cohort over the EA cohort. The only unique CNA identified in this initial analysis that had not been previously linked to PCa was loss of chromosome 4p16.3. 3 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 13, 2017; DOI: 10.1158/0008-5472.CAN-17-0669 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. We have now extended our original CNA studies to a new set of 40 highly tumor- enriched primary PCas and matched benign prostate tissues from AA men using high resolution Affymetrix 6.0 SNP arrays and expression array analysis using RNAs from the same tissues. We have confirmed the specific loss of 4p16.3 described previously (22) and identified a novel tumor suppressor gene, RGS12 at this locus that shows significantly decreased expression in AA PCa but not EA EA PCa. Both in vitro and in vivo data show that RGS12 is a tumor suppressor gene, as would be predicted from its known ability to negatively regulate pro- oncogenic signal transduction. Furthermore, we have found that loss of RGS12 increases expression of MNX1 at least in part by regulating AKT protein levels. Our findings establish a novel oncogenic axis in AA PCa. MATERIALS AND METHODS Prostate and prostate cancer tissue. Tissue samples were obtained from the Human Tissue Acquisition and Pathology Core of the Dan L. Duncan Cancer Center and were collected from fresh radical prostatectomy specimens after obtaining informed consent under a Baylor College of Medicine Institutional Review Board approved protocol and as such followed the principals of the Declaration of Helsinki and the Belmont Report. Cancer tissues include at least 70% tumor tissue and benign tissues were free of cancer on pathological examination. DNAs and RNAs were extracted using a Qiagen DNA/RNA mini kit following the manufacturer’s protocol. Affymetrix 6.0 SNP and Agilent 60K expression arrays. DNAs from AA PCa tissues and matched benign tissue were analyzed using Affymetrix 6.0 SNP arrays by the Albert Einstein College of Medicine Genomics Core. SNP array data were processed using the crlmm package in Bioconductor, with the preprocessing steps for copy number estimation as follows: (1) quantile normalization of the raw intensities (quantile normalizing the SNPs and nonpolymorphic markers separately), (2) genotyping, (3) for total copy number, translating the normalized 4 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 13, 2017; DOI: 10.1158/0008-5472.CAN-17-0669 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. intensities to an estimate of raw copy number by adding the allele-specific summaries. For each of the 1M SNP probes, each tumor profile was centered on the paired normal, in order to generate tumor:normal ratios. Tumor:normal logged values were averaged by gene, and each profile was centered on the median of log ratios across all genes. For heat map presentation, gene-level tumor:normal values were further collapsed into cytobands. When combining datasets from multiple studies, values for each dataset were binned as gain or loss or no change, using a similar approach to that of our previous study (22). For the Lapointe dataset, the standard deviation (SD) of the tumor profile with the smallest SD across cytobands was used as the reference for defining gain or loss events within each cytoband; cytobands with average values greater than +3SD were called as gain, and cytoband values less than −3 SD were called as loss. Gene-level copy alterations for the Taylor dataset were previously binned in that study, with average cytoband log2 ratio>0.6 or <-0.6 being called here as gain or loss, respectively. For our own SNP array datasets (present study and Castro et al. (22)), a log2 of 0.2 was used as the cutoff (similar to that of Castro et al. (22)). Expression array analysis has been described previously (6). GEO accession number pending. Quantitative real-time PCR (Q-RT-PCR).
Load more

Recommended publications
  • RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate
    Published OnlineFirst June 13, 2017; DOI: 10.1158/0008-5472.CAN-17-0669 Cancer Molecular and Cellular Pathobiology Research RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression Yongquan Wang1,2, Jianghua Wang2, Li Zhang2,3, Omer Faruk Karatas2, Longjiang Shao2, Yiqun Zhang4, Patricia Castro2, Chad J. Creighton4,5,and Michael Ittmann2 Abstract African American (AA) men exhibit a relatively high incidence epithelial cells. Notably, RGS12 exhibited potent tumor-suppres- and mortality due to prostate cancer even after adjustment for sor activity in prostate cancer and prostate epithelial cell lines in socioeconomic factors, but the biological basis for this disparity is vitro and in vivo. We found that RGS12 expression correlated unclear. Here, we identify a novel region on chromosome 4p16.3 negatively with the oncogene MNX1 and regulated its expression that is lost selectively in AA prostate cancer. The negative regulator in vitro and in vivo. Further, MNX1 was regulated by AKT activity, of G-protein signaling RGS12 was defined as the target of 4p16.3 and RGS12 expression decreased total and activated AKT levels. deletions, although it has not been implicated previously as a Our findings identify RGS12 as a candidate tumor-suppressor tumor-suppressor gene. RGS12 transcript levels were relatively gene in AA prostate cancer, which acts by decreasing expression of reduced in AA prostate cancer, and prostate cancer cell lines AKT and MNX1, establishing a novel oncogenic axis in this showed decreased RGS12 expression relative to benign prostate disparate disease setting. Cancer Res; 77(16); 1–11.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Characterizing the Mechanisms of Kappa Opioid Receptor Signaling Within Mesolimbic Dopamine Circuitry Katie Reichard a Dissertat
    Characterizing the mechanisms of kappa opioid receptor signaling within mesolimbic dopamine circuitry Katie Reichard A dissertation submitted in partial fulfillment of the degree requirements for the degree of: Doctor of Philosophy University of Washington 2020 Reading Committee: Charles Chavkin, Chair Paul Phillips Larry Zweifel Program Authorized to Confer Degree: Neuroscience Graduate Program TABLE OF CONTENTS Summary/Abstract………………………………………………………………………….……..6 Dedication……………………………………………………………………………….………...9 Chapter 1 The therapeutic potential of the targeting the kappa opioid receptor system in stress- associated mental health disorders……………………………….………………………………10 Section 1.1 Activation of the dynorphin/kappa opioid receptor system is associated with dysphoria, cognitive disruption, and increased preference for drugs of abuse…………………..13 Section 1.2 Contribution of the dyn/KOR system to substance use disorder, anxiety, and depression………………………………………………………………………………………..15 Section 1.3 KORs are expressed on dorsal raphe serotonin neurons and contribute to stress- induced plasticity with serotonin circuitry……………………………………………………….17 Section 1.4 Kappa opioid receptor expression in the VTA contributes to the behavioral response to stress……………………………………………………………………………………....…..19 Section 1.5 Other brain regions contributing to the KOR-mediated response to stress…………23 Section 1.6 G Protein signaling at the KOR …………………………………………………….25 Chapter 2: JNK-Receptor Inactivation Affects D2 Receptor through both agonist action and norBNI-mediated cross-inactivation
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Mx1cre Mediated Rgs12 Conditional Knockout Mice Exhibit Increased
    VC 2013 Wiley Periodicals, Inc. genesis 51:201–209 (2013) TECHNOLOGY REPORT Mx1-Cre Mediated Rgs12 Conditional Knockout Mice Exhibit Increased Bone Mass Phenotype Shuying Yang,1,2* Yi-Ping Li,3 Tongjun Liu,1,4 Xiaoning He,1,5 Xue Yuan,1 Chunyi Li,1 Jay Cao,6 and Yunjung Kim1 1Department of Oral Biology, School of Dental Medicine, University of Buffalo, State University of New York, Buffalo, New York 2Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, University of Buffalo, The State University of New York, Buffalo, New York 3Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, Alabama 4Department of Stomatology, Jinan Central Hospital, Shandong University, Jinan, 250013 People’s Republic of China 5Department of Stomatology, The 4th Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning, 110032, People’s Republic of China 6Human Nutritioin Research Center, USDA ARS Grand Forks, Grand Forks, North Dakota Received 31 August 2012; Revised 14 January 2012; Accepted 16 January 2012 Summary: Regulators of G-protein Signaling (Rgs) Key words: Cre; loxP; FRT; conditional inactivation; Regu- proteins are the members of a multigene family of lator of G protein signaling protein GTPase-accelerating proteins (GAP) for the Galpha subunit of heterotrimeric G-proteins. Rgs proteins play critical roles in the regulation of G protein couple receptor (GPCR) signaling in normal physiology and INTRODUCTION human diseases such as cancer, heart diseases, and inflammation. Rgs12 is the largest protein of the Rgs “Regulators of G-protein signaling,” or Rgs proteins, are a protein family.
    [Show full text]
  • Expression of Regulator of G Protei
    Toll-Like Receptor Signaling Alters the Expression of Regulator of G Protein Signaling Proteins in Dendritic Cells: Implications for G Protein-Coupled Receptor This information is current as Signaling of September 29, 2021. Geng-Xian Shi, Kathleen Harrison, Sang-Bae Han, Chantal Moratz and John H. Kehrl J Immunol 2004; 172:5175-5184; ; doi: 10.4049/jimmunol.172.9.5175 Downloaded from http://www.jimmunol.org/content/172/9/5175 References This article cites 49 articles, 26 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/172/9/5175.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 29, 2021 • Fast Publication! 4 weeks from acceptance to publication *average 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Toll-Like Receptor Signaling Alters the Expression of Regulator of G Protein Signaling Proteins in Dendritic Cells: Implications for G Protein-Coupled Receptor Signaling Geng-Xian Shi,1 Kathleen Harrison,1 Sang-Bae Han,1 Chantal Moratz, and John H.
    [Show full text]
  • Supp Table 6.Pdf
    Supplementary Table 6. Processes associated to the 2037 SCL candidate target genes ID Symbol Entrez Gene Name Process NM_178114 AMIGO2 adhesion molecule with Ig-like domain 2 adhesion NM_033474 ARVCF armadillo repeat gene deletes in velocardiofacial syndrome adhesion NM_027060 BTBD9 BTB (POZ) domain containing 9 adhesion NM_001039149 CD226 CD226 molecule adhesion NM_010581 CD47 CD47 molecule adhesion NM_023370 CDH23 cadherin-like 23 adhesion NM_207298 CERCAM cerebral endothelial cell adhesion molecule adhesion NM_021719 CLDN15 claudin 15 adhesion NM_009902 CLDN3 claudin 3 adhesion NM_008779 CNTN3 contactin 3 (plasmacytoma associated) adhesion NM_015734 COL5A1 collagen, type V, alpha 1 adhesion NM_007803 CTTN cortactin adhesion NM_009142 CX3CL1 chemokine (C-X3-C motif) ligand 1 adhesion NM_031174 DSCAM Down syndrome cell adhesion molecule adhesion NM_145158 EMILIN2 elastin microfibril interfacer 2 adhesion NM_001081286 FAT1 FAT tumor suppressor homolog 1 (Drosophila) adhesion NM_001080814 FAT3 FAT tumor suppressor homolog 3 (Drosophila) adhesion NM_153795 FERMT3 fermitin family homolog 3 (Drosophila) adhesion NM_010494 ICAM2 intercellular adhesion molecule 2 adhesion NM_023892 ICAM4 (includes EG:3386) intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)adhesion NM_001001979 MEGF10 multiple EGF-like-domains 10 adhesion NM_172522 MEGF11 multiple EGF-like-domains 11 adhesion NM_010739 MUC13 mucin 13, cell surface associated adhesion NM_013610 NINJ1 ninjurin 1 adhesion NM_016718 NINJ2 ninjurin 2 adhesion NM_172932 NLGN3 neuroligin
    [Show full text]
  • Supplementary Table 2
    Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942
    [Show full text]
  • Supplementary Table 1
    Supplementary Table 1. 492 genes are unique to 0 h post-heat timepoint. The name, p-value, fold change, location and family of each gene are indicated. Genes were filtered for an absolute value log2 ration 1.5 and a significance value of p ≤ 0.05. Symbol p-value Log Gene Name Location Family Ratio ABCA13 1.87E-02 3.292 ATP-binding cassette, sub-family unknown transporter A (ABC1), member 13 ABCB1 1.93E-02 −1.819 ATP-binding cassette, sub-family Plasma transporter B (MDR/TAP), member 1 Membrane ABCC3 2.83E-02 2.016 ATP-binding cassette, sub-family Plasma transporter C (CFTR/MRP), member 3 Membrane ABHD6 7.79E-03 −2.717 abhydrolase domain containing 6 Cytoplasm enzyme ACAT1 4.10E-02 3.009 acetyl-CoA acetyltransferase 1 Cytoplasm enzyme ACBD4 2.66E-03 1.722 acyl-CoA binding domain unknown other containing 4 ACSL5 1.86E-02 −2.876 acyl-CoA synthetase long-chain Cytoplasm enzyme family member 5 ADAM23 3.33E-02 −3.008 ADAM metallopeptidase domain Plasma peptidase 23 Membrane ADAM29 5.58E-03 3.463 ADAM metallopeptidase domain Plasma peptidase 29 Membrane ADAMTS17 2.67E-04 3.051 ADAM metallopeptidase with Extracellular other thrombospondin type 1 motif, 17 Space ADCYAP1R1 1.20E-02 1.848 adenylate cyclase activating Plasma G-protein polypeptide 1 (pituitary) receptor Membrane coupled type I receptor ADH6 (includes 4.02E-02 −1.845 alcohol dehydrogenase 6 (class Cytoplasm enzyme EG:130) V) AHSA2 1.54E-04 −1.6 AHA1, activator of heat shock unknown other 90kDa protein ATPase homolog 2 (yeast) AK5 3.32E-02 1.658 adenylate kinase 5 Cytoplasm kinase AK7
    [Show full text]
  • Identification of Genomic Targets of Krüppel-Like Factor 9 in Mouse Hippocampal
    Identification of Genomic Targets of Krüppel-like Factor 9 in Mouse Hippocampal Neurons: Evidence for a role in modulating peripheral circadian clocks by Joseph R. Knoedler A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Neuroscience) in the University of Michigan 2016 Doctoral Committee: Professor Robert J. Denver, Chair Professor Daniel Goldman Professor Diane Robins Professor Audrey Seasholtz Associate Professor Bing Ye ©Joseph R. Knoedler All Rights Reserved 2016 To my parents, who never once questioned my decision to become the other kind of doctor, And to Lucy, who has pushed me to be a better person from day one. ii Acknowledgements I have a huge number of people to thank for having made it to this point, so in no particular order: -I would like to thank my adviser, Dr. Robert J. Denver, for his guidance, encouragement, and patience over the last seven years; his mentorship has been indispensable for my growth as a scientist -I would also like to thank my committee members, Drs. Audrey Seasholtz, Dan Goldman, Diane Robins and Bing Ye, for their constructive feedback and their willingness to meet in a frequently cold, windowless room across campus from where they work -I am hugely indebted to Pia Bagamasbad and Yasuhiro Kyono for teaching me almost everything I know about molecular biology and bioinformatics, and to Arasakumar Subramani for his tireless work during the home stretch to my dissertation -I am grateful for the Neuroscience Program leadership and staff, in particular
    [Show full text]
  • Proteins in Receptor-Mediated Cell Signaling Melinda Dale Willard A
    Multiple Domain ‘Nexus’ Proteins in Receptor-Mediated Cell Signaling Melinda Dale Willard A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmacology. Chapel Hill 2006 Approved by: Advisor: Professor David P. Siderovski Reader: Professor T. Kendall Harden Reader: Professor Gary L. Johnson Reader: Professor Michael D. Schaller Reader: Professor John E. Sondek ABSTRACT Melinda Dale Willard Multiple Domain ‘Nexus’ Proteins in Receptor-Mediated Cell Signaling (Under the direction of Dr. David P. Siderovski) Signal transduction is the fundamental biological process of converting changes in extracellular information into changes in intracellular functions. It controls a wide range of cellular activities, from the release of neurotransmitters and hormones, to integrated cellular decisions of proliferation, differentiation, survival, or death. The vast majority of extracellular signaling molecules exert their cellular effects through activation of G protein-coupled receptors (GPCRs); however, the G- protein coupled paradigm is by no means the exclusive mechanism of membrane receptor signal transduction. Polypeptide ligands such as nerve growth factor act exclusively on receptor tyrosine kinase receptors (RTKs) to promote signaling. GPCRs and RTKs both form an interface between extracellular and intracellular physiology by converting hormonal signals into changes in intracellular metabolism and ultimately cell phenotype. Initially, it was thought that GPCRs and RTKs represented linear and distinct signaling pathways that converge on downstream targets to regulate cell division and gene transcription. However, activation of second messenger generating systems do not fully explain the range of effects of GPCR or RTK activation on biological processes such as differentiation and cell growth.
    [Show full text]
  • Oxidized Phospholipids Regulate Amino Acid Metabolism Through MTHFD2 to Facilitate Nucleotide Release in Endothelial Cells
    ARTICLE DOI: 10.1038/s41467-018-04602-0 OPEN Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells Juliane Hitzel1,2, Eunjee Lee3,4, Yi Zhang 3,5,Sofia Iris Bibli2,6, Xiaogang Li7, Sven Zukunft 2,6, Beatrice Pflüger1,2, Jiong Hu2,6, Christoph Schürmann1,2, Andrea Estefania Vasconez1,2, James A. Oo1,2, Adelheid Kratzer8,9, Sandeep Kumar 10, Flávia Rezende1,2, Ivana Josipovic1,2, Dominique Thomas11, Hector Giral8,9, Yannick Schreiber12, Gerd Geisslinger11,12, Christian Fork1,2, Xia Yang13, Fragiska Sigala14, Casey E. Romanoski15, Jens Kroll7, Hanjoong Jo 10, Ulf Landmesser8,9,16, Aldons J. Lusis17, 1234567890():,; Dmitry Namgaladze18, Ingrid Fleming2,6, Matthias S. Leisegang1,2, Jun Zhu 3,4 & Ralf P. Brandes1,2 Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a cau- sal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipo- proteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2- controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
    [Show full text]