Verfügbarkeit: Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase

Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase:

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Bibliographische Detailangaben
1. Verfasser:	Jovanovic, Bogdan (VerfasserIn)
Format:	Abschlussarbeit Buch
Sprache:	English
Veröffentlicht:	Heidelberg 2017
Schlagworte:	Hochschulschrift
Online-Zugang:	Inhaltsverzeichnis Inhaltsverzeichnis
Beschreibung:	iii, 155 Seiten Illustrationen, Diagramme 30 cm

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adam_text	CONTENTS SUMMARY 1 LIST OF FIGURES 5 LIST OF TABLES 7 1 INTRODUCTION 9 1.1 THE CELLULAR STRESS RESPONSE ............................................................. 9 1.1.1 CONTROL OF GENE EXPRESSION DURING STRESS .......................... 9 1.2 REGULATION OF MRNA TRANSLATION ....................................................... 11 1.2.1 MOLECULAR MECHANISM OF MRNA TRANSLATION . .. ....................11 1.3 CONTROL OF TRANSLATION UNDER STRE SS....................................................... 15 1.3.1 INHIBITION OF THE CAP-BINDING COM PLEX .................................... 15 1.3.2 THE EIF2A P A TH W A Y .................................................................... 16 1.3.3 HRI KINASE ............................................................................. 19 1.4 STRESS GRANULES ....................................................................................... 21 1.5 OXIDATIVE STRESS AND REDOX SIGNALING.................................................... 24 1.5.1 OXIDATIVE S TR E S S .......................................................................... 25 1.5.2 TLIIOL-DEPENDENT REDOX SIG N ALIN G ..............................................27 1.5.3 ARSENIC TO X IC ITY .......................................................................... 30 1.6 AIM OF THE S T U D Y ....................................................................................33 2 RESULTS 35 2.1 HRI MEDIATES TRANSLATION SUPPRESSION UPON ARSENITE EXPOSURE . . 35 2.2 HRI CHANGES ITS REDOX STATUS DURING A C TIV A TIO N .................................40 2.2.1 HRI IS OXIDIZED IN CELLS EXPOSED TO ARSENITE . . . ................... 40 2.2.2 HRI FORMS A COVALENT COMPLEX UPON ARSENITE EXPOSURE . . 43 2.3 HRI FORMS A COVALENTLY BOUND DIMER UPON ARSENITE EXPOSURE . . 45 2.3.1 THE HIGH MOLECULAR COMPLEX CONSISTS OF AT LEAST TWO HRI M O LE C U LE S ................................................................... 45 2.3.2 DIMERIZATION IS MEDIATED THROUGH HRI CYSTEINE RESIDUE C 1 3 9 ............................................................................................. 48 2.4 THE IMPORTANCE OF THIOLS IN HRI A C TIV A TIO N ....................................... 50 2.4.1 COVALENT DIMER FORMATION IS NOT IMPORTANT FOR HRI AC TIVATION ....................................................................................... 50 2.4.2 THE IMPORTANCE OF OTHER CYS RESIDUES IN HRI ACTIVATION . 51 2.4.3 OXIDATION OF HRI THIOLS CAUSES LOSS OF HRI HEME BINDING A B I L I T Y ........................................................................................... 55 2.5 HRI INTERACTOME .....................................................................................57 2.5.1 IDENTIFICATION OF PROTEINS TH AT INTERACT WITH H R I ................. 57 2.5.2 VALIDATION OF INTERESTING C A N D ID A TE S ....................................... 61 2.6 TRXL MEDIATES SG FORMATION UPON ARSENITE EX P O SU RE ....................... 69 2.6.1 TRXL IS IM PORTANT FOR SG FORMATION UPON ARSENITE AND NAN3 S T R E S S ..................................................................................69 2.6.2 TRXL IS NOT IM PORTANT FOR HRI A C TIV A TIO N .............................. 72 2.6.3 TRXL IS A SG M A R K E R ....................................................... ... . 74 2.7 TRANSLATION SUPPRESSION IS CRUCIAL FOR CELL SURVIVAL UPON ARSENITE E X P O SU RE ..................................................................................................... 76 2.8 ACUTE TRXRL INHIBITION CAUSES HRI A C TIV A TIO N ................................. 77 2.8.1 AURANOFIN INDUCES HRI DEPENDENT TRANSLATION SUPPRESSION 77 2.8.2 GOPI SUGAR INDUCES HRI DEPENDENT TRANSLATION SUPPRESSION 80 2.8.3 TRXRL INTERACTS WITH H R I ........................................................84 3 DISCUSSION 87 3.1 HRI FORMS A COVALENT DIMER UPON ARSENITE E X P O S U R E ....................... 87 3.2 THE IMPORTANCE OF HRI THIOLS IN HRI ACTIVATION AND HEME BINDING 88 3.3 T RXL IS IM PORTANT FOR SG FORMATION, BUT NOT FOR HRI ACTIVATION UNDER ARSENITE S T R E S S .............................................................................. 91 3.4 ACUTE TRXRL INHIBITION TRIGGERS HRI ACTIVATION ..............................92 3.5 TRANSLATION SUPPRESSION IS CRUCIAL FOR CELL SURVIVAL UPON ARSENITE E X P O SU RE .....................................................................................................93 3.6 SUMMARY AND M O D E L .............................................................................. 95 3.7 FUTURE D IR E C TIO N S .....................................................................................96 3.7.1 DECIPHERING THE COMPLETE REDOX RELAY IN HRI ACTIVATION . 96 3.7.2 ROLE OF TRXRL IN HRI ACTIVATION DURING IRON DEFICIENCY . 98 3.7.3 IDENTIFICATION OF GLOBAL REDOX CHANGES IM PORTANT FOR TRANS LATIONAL C O N T R O L ........................................................................... 99 4 MATERIALS AND METHODS 101 4.1 MATERIALS ................................................................................................101 4.2 M E TH O D S ................................................................................................... 101 4.2.1 CELL C U L T U R E ................................................................................101 4.2.2 CELL C U L T U R E ................................................................................102 4.2.3 TRANSFECTION OF C ELLS...................................................................103 4.2.4 CELL LYSIS PRIOR TO WESTERN BLOT A N ALY SIS ............................... 104 4.2.5 IMMUNOPRECIPITATION WITH GFP B I N D E R ............................... 104 4.2.6 SDS GEL ELECTROPHORESIS AND WESTERN B LO TTIN G .................. 105 4.2.7 POLYSOME PROFILE......................................................................... 105 4.2.8 PUROMYCIN INCO RP O RATIO N .........................................................106 4.2.9 IMMUNOFLUORESCENCE ............................................................... 106 4.2.10 MEASUREMENT OF DEAD CELLS WITH FLOW C Y T O M E T R Y ............... 107 4.2.11 PURIFICATION OF REVERSIBLY OXIDIZED PROTEINS (PROP) . . . 107 4.2.12 PLASMID C O N STRU C TIO N ............................................................... 108 4.2.13 OLIGO P H O S P H O RY LA TIO N ............................................................ 110 4.2.14 L IG A TIO N ..................................................................................... 110 4.2.15 TRANSFORMATION OF B A C TE RIA ................................... 110 4.2.16 COLONY P G R ............................................................................... I L L 4.2.17 QUANTITATIVE R T - P C R ................................... ! ................... I L L 4.2.18 RECOMBINANT PROTEIN P U RIFIC A TIO N .........................................112 4.2.19 ASSESSMENT OF THE HEME BINDING IN H R I ............................... 112 4.2.20 GEL S TA IN IN G ............................................................................... 112 4.2.21 STATISTICAL A N A LY S IS .................................................................. 113 ABBREVIATIONS 115 ACKNOWLEDGMENTS 119 BIBLIOGRAPHY 121 5 APPENDIX 143 5.1 SUPPLEMENTARY DATA ............................................................................143 5.2 MATERIALS USED IN THIS S T U D Y ...............................................................152 5.2.1 D ISP O SA B LE S............................................................................... 152 5.2.2 C H EM ICA LS.................................................................................. 153 5.2.3 A NTIBODIES.................................................................................. 156 5.2.4 TECHNICAL E Q U IP M E N T............................................................... 157 5.2.5 SIRNAS ..................................................................................... 159 5.2.6 O LIG O S ........................................................................................ 160 5.2.7 P LASM ID S..................................................................................... 162
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spelling	Jovanovic, Bogdan Verfasser (DE-588)1159997101 aut Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase presented by Bogdan Jovanovic, M.Sc. in Molecular Biosciences Heidelberg 2017 iii, 155 Seiten Illustrationen, Diagramme 30 cm txt rdacontent n rdamedia nc rdacarrier Dissertation Ruperto-Carola University of Heidelberg 2017 (DE-588)4113937-9 Hochschulschrift gnd-content B:DE-101 application/pdf http://d-nb.info/1159996768/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030665577&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis
spellingShingle	Jovanovic, Bogdan Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase
subject_GND	(DE-588)4113937-9
title	Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase
title_auth	Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase
title_exact_search	Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase
title_full	Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase presented by Bogdan Jovanovic, M.Sc. in Molecular Biosciences
title_fullStr	Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase presented by Bogdan Jovanovic, M.Sc. in Molecular Biosciences
title_full_unstemmed	Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase presented by Bogdan Jovanovic, M.Sc. in Molecular Biosciences
title_short	Mechanism of arsenite-induced activation of heme-regulated inhibitor kinase
title_sort	mechanism of arsenite induced activation of heme regulated inhibitor kinase
topic_facet	Hochschulschrift
url	http://d-nb.info/1159996768/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030665577&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
work_keys_str_mv	AT jovanovicbogdan mechanismofarseniteinducedactivationofhemeregulatedinhibitorkinase

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