DOCSLIB.ORG

Activatio of Ovel Sig Al Tra Sductio Pathways by Fp Receptors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Activatio of Ovel Sig Al Tra Sductio Pathways by Fp Receptors Activation of Novel Signal Transduction Pathways by FP Receptors: The G-Protein Coupled Receptors for Prostaglandin F2alpha Item Type text; Electronic Dissertation Authors Xu, Wei Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 24/09/2021 06:48:12 Link to Item http://hdl.handle.net/10150/195223 ACTIVATIO OF OVEL SIGAL TRASDUCTIO PATHWAYS BY FP RECEPTORS: THE GPROTEI COUPLED RECEPTORS FOR PROSTAGLADI F2Α by WeiXu ADissertationSubmittedtothe Facultyofthe DEPARTMETOF PHARMACOLOGY & TOXICOLOGY InPartial FulfillmentoftheRequirements For theDegreeof DOCTOROF PHILOSOPHY IntheGraduateCollege THEUIVERSITYOFARIZOA 2007 2 THEUNIVERSITY OF ARIZONA® GRADUATECOLLEGE Asmembersofthe Final ExaminationCommittee,wecertifythatwehavereadthe dissertationpreparedby WeiXu_______________________________________________ Entitled: Activation of Novel Signal Transduction Pathways by FP Receptors: the G-Protein Coupled Receptors for Prostaglandin F2α and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy _______________________________________________ Apr.12th,2007 John W.Regan Date _______________________________________________ Apr.12th,2007 John W.Bloom Date _______________________________________________ Apr.12th,2007 TimBowden Date _______________________________________________ Apr.12th,2007 RogerMiesfeld Date _______________________________________________ Apr.12th,2007 DanStamer Date Finalapprovalandacceptanceofthisdissertation iscontingentuponthecandidate’s submissionofthefinalcopyofthedissertationtotheGraduateCollege.I herebycertify that Ihavereadthisdissertationpreparedundermy directionandrecommendthatitbe acceptedasfulfillingthe dissertationrequirement. _________John W.Regan_________________________Apr.12th,2007 DissertationDirector Date 3 STATEMETBYAUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the University Library tobemadeavailabletoborrowersunderrulesofthe Library. Brief quotations from this dissertation are allowable without special permission,provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances,however,permissionmustbeobtainedfromtheauthor. SIGNED: WeiXu 4 ACKOWLEDGEMETS First, I would like to thank Dr. John W. Regan for the support and guidance he has provided throughout my doctoral studies.Dr.Regan has given me many opportunities to expand my horizons by allowing me to have a lot of freedom in my research. I venerate Dr.Regan’s intelligence, work ethic,scientific integrity as well as attention to detail; they aresecondtononeandit iseasytoseewhyheis verysuccessful. I would also like to thank my committee members Doctors John Bloom,Tim Bowden, RogerMiesfeldand Dan Stamerfortheirscientific andprofessionalsupport. I would like to thank Dr. Chiling Chou for her time,experience and prospect in helping me with my studies. We worked together to get the results presented in this thesis. Withoutherhelp,Icannotimagehow Ican achievesomuchinmy graduatestudy. I would like to thank all the other folks in the Regan lab; Alfred, George, Dinesh, Hiromichi,Tony,Chi-ling and Amy for their help over the years. I would also like to thank Dr.Vallancourt for his help in my projects.It is his idea and vision to help this projecttakeoff. Last,and certainly not least,I would like to thank my parents, Kanglin Xu and Yixin Shenaswellasmywife ZhouandsonWilliamfortheirsupportoverthe years. 5 DEDICATIO This dissertation is dedicated to my family,especially my parents and parents-in-laws, who over the years have supported my efforts with great patience,support and love. I would also like to thank my wife Zhou and son William for their support over these years. 6 TABLEOFCOTETS LISTOF FIGURES ............................................................................................................ 8 LISTOFTABLES............................................................................................................ 10 LISTOFABBREVIATIONS........................................................................................... 11 ABSTRACT.............................................................................................................................................13 CHAPTERONE: INTRODUCTION,PURPOSEANDAIMS....................................... 15 1.1 Introduction............................................................................................................. 16 1.2Prostanoidreceptors................................................................................................ 19 1.3FPreceptors ............................................................................................................ 20 1.4Purposeandaims ................................................................................................... 24 CHAPTER TWO: IDENTIFICATION OF GENES REGULATED BY THE ACTIVATION OF FP PROSTANOID RECEPTOR UTILIZING CDNA MICROARRAYTECHNOLOGY .................................................................................. 27 2.1 Introduction ............................................................................................................ 28 2.2Experimentalprocedures ........................................................................................ 29 2.3Results..................................................................................................................... 32 2.4Discussion............................................................................................................... 34 CHAPTER THREE: CHARACTERIZATION OF THE SIGNALING PATHWAYS INVOLVED IN THE REGULATION OF EGR-1 EXPRESSION BY THE ACTIVATIONOF FPPROSTANOIDRECEPTORS .................................................... 43 3.1 Introduction ............................................................................................................ 44 3.2Experimentalprocedures ........................................................................................ 46 7 TABLEOFCOTETS-Continued 3.3Results...................................................................................................................... 47 3.4Discussion................................................................................................................ 50 CHAPTER FOUR: CHARACTERIZATION OF THE SIGNALING PATHWAYS INVOLVED IN THE REGULATION OF CYR61 EXPRESSION BY THE ACTIVATIONOF FPPROSTANOIDRECEPTORS .................................................... 57 4.1 Introduction............................................................................................................. 58 4.2Experimentalprocedures ........................................................................................ 59 4.3Results..................................................................................................................... 64 4.4Discussion............................................................................................................... 68 CHAPTER FIVE: CHARACTERIZATION OF THE SIGNALING PATHWAYS INVOLVED IN THE REGULATION OF CTGF EXPRESSION BY THE ACTIVATIONOF FPPROSTANOIDRECEPTORS .................................................... 80 5.1 Introduction............................................................................................................. 81 5.2Experimentalprocedures ........................................................................................ 83 5.3Results..................................................................................................................... 85 5.4Discussion...............................................................................................................89 CHAPTERSIX:CONCLUSIONSAND FUTURESTUDIES ..................................... 102 6.1Conclusions........................................................................................................... 103 6.2Futurestudies........................................................................................................ 107 REFERENCES ............................................................................................................... 110 8 LISTOFFIGURES Figure 1.1 Schematic pathways of eicosanoid biosynthesis from arachidonic acid release andmetabolism ............................................................................................................. 18 Figure1.2SignaltransductionpathwaysthroughtheFPreceptor ................................... 23 Figure2.1 FunctionClassificationofgenesidentifiedby cDNAmicroarray analysis ....39 Figure2.2Northern Blottinganalysisof genesidentifiedbycDNAmicroarrayanalysis41 Figure2.3Western Blottinganalysisof genesidentifiedbycDNAmicroarray analysis 42 Figure 3.1 MEK1/2 is involved in the gene regulation of EGR-1 through the FP receptor ......................................................................................................................................
Load more

Recommended publications
  • Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse
    Welcome to More Choice CD Marker Handbook For more information, please visit: Human bdbiosciences.com/eu/go/humancdmarkers Mouse bdbiosciences.com/eu/go/mousecdmarkers Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse CD3 CD3 CD (cluster of differentiation) molecules are cell surface markers T Cell CD4 CD4 useful for the identification and characterization of leukocytes. The CD CD8 CD8 nomenclature was developed and is maintained through the HLDA (Human Leukocyte Differentiation Antigens) workshop started in 1982. CD45R/B220 CD19 CD19 The goal is to provide standardization of monoclonal antibodies to B Cell CD20 CD22 (B cell activation marker) human antigens across laboratories. To characterize or “workshop” the antibodies, multiple laboratories carry out blind analyses of antibodies. These results independently validate antibody specificity. CD11c CD11c Dendritic Cell CD123 CD123 While the CD nomenclature has been developed for use with human antigens, it is applied to corresponding mouse antigens as well as antigens from other species. However, the mouse and other species NK Cell CD56 CD335 (NKp46) antibodies are not tested by HLDA. Human CD markers were reviewed by the HLDA. New CD markers Stem Cell/ CD34 CD34 were established at the HLDA9 meeting held in Barcelona in 2010. For Precursor hematopoetic stem cell only hematopoetic stem cell only additional information and CD markers please visit www.hcdm.org. Macrophage/ CD14 CD11b/ Mac-1 Monocyte CD33 Ly-71 (F4/80) CD66b Granulocyte CD66b Gr-1/Ly6G Ly6C CD41 CD41 CD61 (Integrin b3) CD61 Platelet CD9 CD62 CD62P (activated platelets) CD235a CD235a Erythrocyte Ter-119 CD146 MECA-32 CD106 CD146 Endothelial Cell CD31 CD62E (activated endothelial cells) Epithelial Cell CD236 CD326 (EPCAM1) For Research Use Only.
    [Show full text]
  • An Endocytosis Pathway Initiated Through Neuropilin-1 and Regulated by Nutrient Availability
    ARTICLE Received 18 Apr 2014 | Accepted 2 Aug 2014 | Published 3 Oct 2014 DOI: 10.1038/ncomms5904 An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability Hong-Bo Pang1, Gary B. Braun1,2, Tomas Friman1,2, Pedro Aza-Blanc1, Manuel E. Ruidiaz1, Kazuki N. Sugahara1,3, Tambet Teesalu1,4 & Erkki Ruoslahti1,2 Neuropilins (NRPs) are trans-membrane receptors involved in axon guidance and vascular development. Many growth factors and other signalling molecules bind to NRPs through a carboxy (C)-terminal, basic sequence motif (C-end Rule or CendR motif). Peptides with this motif (CendR peptides) are taken up into cells by endocytosis. Tumour-homing CendR peptides penetrate through tumour tissue and have shown utility in enhancing drug delivery into tumours. Here we show, using RNAi screening and subsequent validation studies, that NRP1-mediated endocytosis of CendR peptides is distinct from known endocytic pathways. Ultrastructurally, CendR endocytosis resembles macropinocytosis, but is mechanistically different. We also show that nutrient-sensing networks such as mTOR signalling regulate CendR endocytosis and subsequent intercellular transport of CendR cargo, both of which are stimulated by nutrient depletion. As CendR is a bulk transport pathway, our results suggest a role for it in nutrient transport; CendR-enhanced drug delivery then makes use of this natural pathway. 1 Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA. 2 Center for Nanomedicine, Department of Cell, Molecular and Developmental Biology, University of California Santa Barbara, Santa Barbara, California 93106-9610, USA. 3 Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
    [Show full text]
  • Microrna-320A Inhibits Tumor Invasion by Targeting Neuropilin 1 and Is Associated with Liver Metastasis in Colorectal Cancer
    ONCOLOGY REPORTS 27: 685-694, 2012 microRNA-320a inhibits tumor invasion by targeting neuropilin 1 and is associated with liver metastasis in colorectal cancer YUJUN ZHANG1, XIANGJUN HE1, YULAN LIU1,2, YINGJIANG YE3, HUI ZHANG3, PEIYING HE1, QI ZHANG1, LINGYI DONG3, YUJING LIU1 and JIANQIANG DONG1 1Institute of Clinical Molecular Biology, and Departments of 2Gastroenterology and 3General Surgery, Peking University, People's Hospital, Beijing 100044, P.R. China Received September 13, 2011; Accepted October 26, 2011 DOI: 10.3892/or.2011.1561 Abstract. MicroRNAs (miRNAs) have been implicated Introduction in regulating diverse cellular pathways. Although there is emerging evidence that various miRNAs function as onco- Colorectal cancer (CRC) is the second most common cause genes or tumor suppressors in colorectal cancer (CRC), the role of cancer-related death worldwide (1). Approximately 50% of of miRNAs in mediating liver metastasis remains unexplored. patients diagnosed with CRC die as a result of complications The expression profile of miRNAs in liver metastasis and from distant metastases, which occur mainly in the liver. The primary CRC tissues was analyzed by miRNA microarrays occurrence of liver metastasis ranges from 20% in stage II to and verified by real-time polymerase chain reaction (PCR). 70% in stage IV CRC patients, according to the UICC stage In 62 CRC patients, the expression levels of miR-320a were guidelines. Of all patients who die of advanced colorectal determined by real-time PCR, and the effects on migration and cancer (ACRC), 60-70% display liver metastasis (2). Metastasis invasion of miR-320a were determined using a transwell assay. to the liver is the major cause of death in CRC patients (3).
    [Show full text]
  • Transcription Factor IRF4 Promotes CD8 T Cell Exhaustion and Limits
    Article Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory- like T Cells during Chronic Infection Graphical Abstract Authors Kevin Man, Sarah S. Gabriel, Yang Liao, ..., Mark A. Febbraio, Wei Shi, Axel Kallies Correspondence [email protected] In Brief During chronic stimulation, CD8+ T cells acquire an exhausted phenotype characterized by expression of inhibitory receptors, loss of effector function, and metabolic impairments. Man et al. have identified a transcriptional module consisting of the TCR-induced transcription factors IRF4, BATF, and NFATc1 that drives T cell exhaustion and impairs memory T cell development. Highlights d High IRF4 mediates T cell exhaustion including expression of inhibitory receptors d TCR-responsive transcription factors IRF4, BATF, and NFAT form a transcriptional circuit d Low IRF4 reduces T cell exhaustion and promotes formation of TCF1+ memory-like T cells Man et al., 2017, Immunity 47, 1129–1141 December 19, 2017 Crown Copyright ª 2017 Published by Elsevier Inc. https://doi.org/10.1016/j.immuni.2017.11.021 Immunity Article Transcription Factor IRF4 Promotes CD8+ TCell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection Kevin Man,1,2,10,11 Sarah S. Gabriel,1,8,9,10 Yang Liao,1,2 Renee Gloury,1,8,9 Simon Preston,1,2 Darren C. Henstridge,3 Marc Pellegrini,1,2 Dietmar Zehn,4 Friederike Berberich-Siebelt,5,6 Mark A. Febbraio,7 Wei Shi,1,2 and Axel Kallies1,8,9,12,* 1The Walter and Eliza Hall Institute of Medical Research, 1G Royal
    [Show full text]
  • Association Between Tfh and PGA in Children with Henoch–Schönlein Purpura
    Open Medicine 2021; 16: 986–991 Research Article Miao Meihua, Li Xiaozhong, Wang Qin, Zhu Yunfen, Cui Yanyan, Shao Xunjun* Association between Tfh and PGA in children with Henoch–Schönlein purpura https://doi.org/10.1515/med-2021-0318 in the HSP group showed no statistical difference com- received May 30, 2019; accepted June 7, 2021 pared with that in the acute respiratory infection and the (P < ) Abstract surgery control 0.05 . Conclusion ‒ Objective ‒ The aim of this study was to investigate the Increased activity of Tfh cells, which is roles of follicular helper CD4+ T cells (Tfh) and serum closely related to mucosal immunity, may be a major contributor in the elevation of PGA-IgA, and Tfh cells anti-α-1,4-D-polygalacturonic acid (PGA) antibody in the - pathogenesis of Henoch–Schönlein purpura (HSP). and PGA IgA are closely related to the occurrence of HSP. Methods ‒ ELISA was performed to determine serum Keywords: Henoch–Schönlein purpura, follicular helper - - + PGA IgA and PGA IgG. Flow cytometry was utilized to CD4 T cells, α-1,4-D-polygalacturonic acid, immunity determine the peripheral CD4+ CXCR5+ and CD4+ CXCR5+ ICOS+ Tfh cells. Real-time PCR was conducted to deter- mine the expression of Bcl-6 gene. Then the change of Tfh cells was analyzed, together with the association 1 Introduction with the anti-PGA antibody as well as the roles in the – ( ) pathogenesis of HSP. Henoch Schönlein purpura HSP , now known as IgA Results ‒ Compared with the cases with acute respira- vasculitis, is a common systemic disease in children. A tory
    [Show full text]
  • Noncanonical Role of Transferrin Receptor 1 Is Essential for Intestinal Homeostasis
    Noncanonical role of transferrin receptor 1 is essential for intestinal homeostasis Alan C. Chena, Adriana Donovanb, Renee Ned-Sykesc, and Nancy C. Andrewsa,d,1 aDepartment of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC 27705; bDivision of Pharmacology and Preclinical Biology, Scholar Rock, Cambridge, MA 02142; cDivision of Laboratory Systems, Center for Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention, Atlanta, GA 30333; and dDepartment of Pediatrics, Duke University School of Medicine, Durham, NC 27705 Contributed by Nancy C. Andrews, August 4, 2015 (sent for review June 16, 2015; reviewed by Jerry Kaplan and Ramesh A. Shivdasani) Transferrin receptor 1 (Tfr1) facilitates cellular iron uptake through Surprisingly, the mice showed marked induction of genes asso- receptor-mediated endocytosis of iron-loaded transferrin. It is ex- ciated with epithelial–mesenchymal transition in IECs, suggest- pressed in the intestinal epithelium but not involved in dietary iron ing that Tfr1 normally acts to suppress this cell fate change. absorption. To investigate its role, we inactivated the Tfr1 gene There was also abnormal accumulation of lipids, similar to mice selectively in murine intestinal epithelial cells. The mutant mice had lacking transcription factor Plagl2, and increased expression of severe disruption of the epithelial barrier and early death. There stem cell markers. was impaired proliferation of intestinal epithelial cell progenitors, aberrant lipid handling, increased mRNA expression of stem cell Results markers, and striking induction of many genes associated with Conditional Deletion of Tfr1 in IECs. We developed Tfr1fl/fl mice epithelial-to-mesenchymal transition. Administration of parenteral carrying loxP sites flanking Tfr1 exons 3–6(Fig.
    [Show full text]
  • Transcriptome Profiling and Differential Gene Expression In
    G C A T T A C G G C A T genes Article Transcriptome Profiling and Differential Gene Expression in Canine Microdissected Anagen and Telogen Hair Follicles and Interfollicular Epidermis Dominique J. Wiener 1,* ,Kátia R. Groch 1 , Magdalena A.T. Brunner 2,3, Tosso Leeb 2,3 , Vidhya Jagannathan 2 and Monika M. Welle 3,4 1 Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Science, Texas A&M University, College Station, TX 77843, USA; [email protected] 2 Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; [email protected] (M.A.T.B.); [email protected] (T.L.); [email protected] (V.J.) 3 Dermfocus, Vetsuisse Faculty, University Hospital of Bern, 3010 Bern, Switzerland; [email protected] 4 Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland * Correspondence: [email protected]; Tel.: +1-979-862-1568 Received: 30 June 2020; Accepted: 3 August 2020; Published: 4 August 2020 Abstract: The transcriptome profile and differential gene expression in telogen and late anagen microdissected hair follicles and the interfollicular epidermis of healthy dogs was investigated by using RNAseq. The genes with the highest expression levels in each group were identified and genes known from studies in other species to be associated with structure and function of hair follicles and epidermis were evaluated. Transcriptome profiling revealed that late anagen follicles expressed mainly keratins and telogen follicles expressed GSN and KRT15. The interfollicular epidermis expressed predominately genes encoding for proteins associated with differentiation. All sample groups express genes encoding for proteins involved in cellular growth and signal transduction.
    [Show full text]
  • Identification of Cell-Surface Proteins Endocytosed by Human Brain
    pharmaceutics Article Identification of Cell-Surface Proteins Endocytosed by Human Brain Microvascular Endothelial Cells In Vitro Shingo Ito 1,2,3, Mariko Oishi 2, Seiryo Ogata 3, Tatsuki Uemura 3, Pierre-Olivier Couraud 4, Takeshi Masuda 1,2,3 and Sumio Ohtsuki 1,2,3,* 1 Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; [email protected] (S.I.); [email protected] (T.M.) 2 Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; [email protected] 3 Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; [email protected] (S.O.); [email protected] (T.U.) 4 Institut Cochin, Universite de Paris, Inserm U1016, CNRS UMR8104, 22 rue Méchain, 75014 Paris, France; [email protected] * Correspondence: [email protected]; Tel.: +81-96-371-4323 Received: 30 April 2020; Accepted: 18 June 2020; Published: 23 June 2020 Abstract: Cell-surface proteins that can endocytose into brain microvascular endothelial cells serve as promising candidates for receptor-mediated transcytosis across the blood–brain barrier (BBB). Here, we comprehensively screened endocytic cell-surface proteins in hCMEC/D3 cells, a model of human brain microvascular endothelial cells, using surface biotinylation methodology and sequential window acquisition of all theoretical fragment-ion spectra-mass spectrometry (SWATH-MS)-based quantitative proteomics. Using this method, we identified 125 endocytic cell-surface proteins from hCMEC/D3 cells.
    [Show full text]
  • Development of Transferrin Receptor Aptamers As Drug Delivery Vehicles for the Treatment of Brain Metastases
    ISSN: 2514-3247 Aptamers, 2018, Vol 2, 15–27 REVIEW Development of transferrin receptor aptamers as drug delivery vehicles for the treatment of brain metastases Joanna Macdonald1, Giovanni Mandarano1, Rakesh Naduvile Veedu2,3, and Sarah Shigdar1,4,* 1School of Medicine Deakin University, Geelong, VIC, Australia- 3216; 2Centre for Comparative Genomics, Murdoch University, Perth, WA, Australia-6150; 3Perron Institute for Neurological and Translational Science, Perth, WA, Australia – 6009; 4Centre for Molecular and Medical Research, Deakin University, Geelong, VIC, Australia- 3216 *Correspondence to: Sarah Shigdar, E-mail: [email protected] Received: 15 December 2017 | Revised: 24 April 2018 | Accepted: 27 April 2018 | Published: 27 April 2018 © Copyright The Author(s). This is an open access article, published under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0). This license permits non-commercial use, distribution and reproduction of this article, provided the original work is appropriately acknowledged, with correct citation details. ABSTRACT Affecting approximately up to 10–40% of all cancer patients, the prognosis for patients suffering from meta- static brain tumours is poor. Treatment of these metastatic tumours is greatly hindered by the presence of the blood brain barrier which restricts the overwhelming majority of small molecules from entering the brain. A novel approach to overcome this barrier is to target receptor mediated transport mechanisms present on the endothelial cell membranes, in particular the transferrin receptor. Given their specificity, safety profile and stability, nucleic acid-based therapeutics are ideal for this purpose. This review explores the development of bifunctional aptamers for the treatment of brain metastases.
    [Show full text]
  • Circadian Rhythm of Transferrin Receptor 1 Gene Expression Controlled by C-Myc in Colon Cancer–Bearing Mice
    Published OnlineFirst July 14, 2010; DOI: 10.1158/0008-5472.CAN-10-0184 Molecular and Cellular Pathobiology Cancer Research Circadian Rhythm of Transferrin Receptor 1 Gene Expression Controlled by c-Myc in Colon Cancer–Bearing Mice Fumiyasu Okazaki1, Naoya Matsunaga1, Hiroyuki Okazaki1, Naoki Utoguchi2, Ryo Suzuki2, Kazuo Maruyama2, Satoru Koyanagi1, and Shigehiro Ohdo1 Abstract The abundance of cell surface levels of transferrin receptor 1 (TfR1), which regulates the uptake of iron- bound transferring, correlates with the rate of cell proliferation. Because TfR1 expression is higher in cancer cells than in normal cells, it offers a target for cancer therapy. In this study, we found that the expression of TfR1 in mouse colon cancer cells was affected by the circadian organization of the molecular clock. The core circadian oscillator is composed of an autoregulatory transcription-translation feedback loop, in which CLOCK and BMAL1 are positive regulators and the Period (Per), Cryptochrome (Cry), and Dec genes act as negative regulators. TfR1 in colon cancer–bearing mice exhibited a 24-hour rhythm in mRNA and protein levels. Luciferase reporter analysis and chromatin immunoprecipitation experiments suggested that the clock-controlled gene c-MYC rhythmically activated the transcription of the TfR1 gene. Platinum incorporation into tumor DNA and the antitumor efficacy of transferrin-conjugated liposome-delivered oxaliplatin could be enhanced by drug administration at times when TfR1 expression increased. Our findings suggest that the 24-hour rhythm of TfR1 expression may form an important aspect of strategies for TfR1-targeted cancer therapy. Cancer Res; 70(15); 6238–46. ©2010 AACR. Introduction metabolism, respiration, and DNA synthesis.
    [Show full text]
  • Lab 06 Transferrin Receptor
    Laboratory Procedure Manual Analyte: Soluble Transferrin Receptor Matrix: Serum Method: Transferrin Receptor - Hitachi 912® Method No: Revised: as performed by: Inorganic Toxicology and Nutrition Branch Division of Laboratory Sciences National Center for Environmental Health Contact: Dr. Christine Pfeiffer Dr. Eric J. Sampson, Director Division of Laboratory Sciences Important Information for Users CDC periodically refines these laboratory methods. It is the responsibility of the user to contact the person listed on the title page of each write-up before using the analytical method to find out whether any changes have been made and what revisions, if any, have been incorporated. Soluble Transferrin Receptor in Serum NHANES 2003-2004 Public Release Data Set Information This document details the Lab Protocol for NHANES 2003-2004 data. A tabular list of the released analytes follows: Lab Analyte SAS Label Number l06_c LBXTFR Transferrin receptor Page 2 of 12 Soluble Transferrin Receptor in Serum NHANES 2003-2004 1. Summary of Test Principle and Clinical Relevance The method principle for measurement of soluble transferrin receptor (sTfR) is immuno-turbidimetry using Roche kits on the Hitachi 912 clinical analyzer. Latex bound anti-sTfR antibodies react with the antigen in the sample to form an antigen/antibody complex. Following agglutination, this is measured turbidimetrically. The transferrin receptor is an integral membrane glycoprotein having a molecular weight of 190 kilodaltons (kD). It consists of two identical subunits linked by disulfide bridges. Each of the monomers has an 85 kD C-terminal component which can bind an iron-laden transferrin molecule. Proteolysis leads to the soluble form of the transferrin receptor.
    [Show full text]
  • Dysregulated Iron Metabolism in Polycythemia Vera: Etiology and Consequences
    Leukemia (2018) 32:2105–2116 https://doi.org/10.1038/s41375-018-0207-9 REVIEW ARTICLE Chronic myeloproliferative neoplasms Dysregulated iron metabolism in polycythemia vera: etiology and consequences 1 1 1 2 3 1 Yelena Z. Ginzburg ● Maria Feola ● Eran Zimran ● Judit Varkonyi ● Tomas Ganz ● Ronald Hoffman Received: 17 May 2018 / Revised: 7 June 2018 / Accepted: 18 June 2018 / Published online: 24 July 2018 © The Author(s) 2018. This article is published with open access Abstract Polycythemia vera (PV) is a chronic myeloproliferative neoplasm. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease. The co-existence of iron deficiency and polycythemia presents a physiological disconnect. Hepcidin, the master regulator of iron metabolism, is regulated by circulating iron levels, erythroblast secretion of erythroferrone, and inflammation. Both decreased circulating iron and increased erythroferrone levels, which occur as a consequence of erythroid hyperplasia in PV, are anticipated to suppress hepcidin and enable recovery from iron deficiency. Inflammation which accompanies PV is likely to counteract hepcidin suppression, but the relatively low serum ferritin levels observed suggest that inflammation is not a major contributor to the dysregulated iron metabolism. Furthermore, potential fi 1234567890();,: 1234567890();,: defects in iron absorption, aberrant hypoxia sensing and signaling, and frequency of bleeding to account for iron de ciency in PV patients have not been fully elucidated. Insufficiently suppressed hepcidin given the degree of iron deficiency in PV patients strongly suggests that disordered iron metabolism is an important component of the pathobiology of PV. Normalization of hematocrit levels using therapeutic phlebotomy is the most common approach for reducing the incidence of thrombotic complications, a therapy which exacerbates iron deficiency, contributing to a variety of non-hematological symptoms.
    [Show full text]