Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth:
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| Main Author: | |
|---|---|
| Format: | Thesis Book |
| Language: | English |
| Published: |
2011
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| Subjects: | |
| Online Access: | Volltext https://nbn-resolving.org/urn:nbn:de:bvb:19-154659 Inhaltsverzeichnis |
| Physical Description: | VI, 182 S. Ill., graph. Darst. |
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MARC
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| 100 | 1 | |a Hellfritsch, Juliane |e Verfasser |4 aut | |
| 245 | 1 | 0 | |a Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth |c Juliane Hellfritsch |
| 264 | 1 | |c 2011 | |
| 300 | |a VI, 182 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 502 | |a München, Univ., Diss., 2011 | ||
| 655 | 7 | |0 (DE-588)4113937-9 |a Hochschulschrift |2 gnd-content | |
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| 856 | 4 | 1 | |u http://edoc.ub.uni-muenchen.de/15465/ |x Verlag |z kostenfrei |3 Volltext |
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| 912 | |a ebook | ||
| 999 | |a oai:aleph.bib-bvb.de:BVB01-025876299 | ||
Record in the Search Index
| _version_ | 1804150180947165184 |
|---|---|
| adam_text | IMAGE 1
I
TABLE O F CONTENTS
1. INTRODUCTION 1
1.1. THE MAMMALIAN THIOREDOXIN FAMILY 1
1.1.1. THIOREDOXINS 2
1.1.2. THIOREDOXIN REDUCTASES 2
1.1.3. SELENIUM IS ESSENTIAL FOR THIOREDOXIN REDUCTASE ACTIVITY 3
1.2. MITOCHONDRIAL THIOREDOXIN REDUCTASE 5
1.2.1. STRUCTURE AND FUNCTION OF TXNRD2 5
1.2.2. IMPLICATION OF TXNRD2 IN MITOCHONDRIAL METABOLISM 7
1.2.3. TARGETED DELETION OF TRX2 AND TXNRD2 9
1.3. TUMOUR BIOLOGY: HOW CANCER ARISES 11
1.3.1. THE MULTI-STEP PROCESS OF CANCER 11
1.3.2. TUMOUR VASCULARISATION: THE ANGIOGENIC SWITCH 12
1.3.3. VASCULAR ENDOTHELIAL GROWTH FACTOR IN TUMOUR ANGIOGENESIS 14
1.3.4. HYPOXIA AND HIF-SIGNALLING IN TUMOUR BIOLOGY 16
1.3.5. IMPLICATION OF MITOCHONDRIA IN TUMOUR PROGRESSION 22
1.4. THIOREDOXIN REDUCTASES IN RELATION TO CANCER AND HIF-SIGNALLING 25
1.5. INTENTION OF THE PRESENT WORK 27
2. MATERIALS A N D METHODS 2 8
2.1. MATERIALS 28
2.2. METHODS 38
2.2.1. CELL CULTURE TECHNIQUES AND RELATED ASSAYS 38
2.2.2. FLOW CYTOMETRY 45
2.2.3. HIGH-RESOLUTION RESPIROMETRY 48
2.2.4. MOLECULAR BIOLOGY TECHNIQUES 50
2.2.5. GENE TRANSFER METHODS 58
2.2.6. PROTEIN BIOCHEMISTRY 60
2.2.7. BIOCHEMICAL ASSAYS 64
2.2.8. TUMOUR TRANSPLANTATION PROTOCOLS 68
2.3. STATISTICS 70
HTTP://D-NB.INFO/1034315455
IMAGE 2
II
3. RESULTS 71
3.1. LONG-TERM EFFECTS OF TXNRD2-DELETION IN MURINE FIBROBLASTS 71
3.1.1. CHARACTERISATION OF IMMORTALISED FIBROBLASTS LACKING TXNRD2 71
3.1.2. GSH-DEPLETION IS ASSOCIATED WITH INCREASED ROS LEVELS IN
TXNRD2-DEFICIENT CELLS 72
3.1.3. CELLS RESPOND TO TXNRD2 DELETION BY UPREGULATING OTHER REDOX
ENZYMES 73
3.1.4. STRUCTURE AND FUNCTIONALITY OF MITOCHONDRIA IN TXNRD2-DEFICIENT
CELLS 76
3.1.5. RESPIRATORY CAPACITY OF TXNRD2-DEFICIENT CELLS 79
3.1.6. METABOLIC CHANGES DUE TO TXNRD2-DELETION 81
3.2. STUDIES OF THE IMPACT OF TXNRD2-DELETION IN TRANSFORMED CELLS IN
VITRO 85
3.2.1. GENERATION OF TRANSFORMED TXNRD2-KNOCKOUT CELLS 85
3.2.2. DELETION OF TXNRD2 IMPAIRS COLONY FORMATION CAPACITY OF TUMOUR
CELLS 86
3.2.3. GENERATION AND CHARACTERISATION OF CLONAL SINGLE-CELL LINES 90
3.2.4. ANALYSIS OF MITOCHONDRIAL PARAMETERS AND CELLULAR METABOLISM
FOLLOWING TRANSFORMATION OF TXNRD2-KNOCKOUT CELLS 93
3.3. RELEVANCE OF TXNRD2 FOR IN VIVO TUMOUR GROWTH 96
3.3.1. LOSS OF TXNRD2 LIMITS TUMOUR GROWTH 96
3.3.2. HISTOLOGICAL ANALYSIS OF TXNRD2-DEFICIENT TUMOURS 98
3.3.3. QUANTIFICATION OF APOPTOTIC CELLS AND NECROTIC AREA IN TUMOUR
SECTIONS 98
3.3.4. IMPAIRED TUMOUR GROWTH DUE TO RESTRICTED PROLIFERATION OF TUMOUR
CELLS 100
3.3.5. LOSS OF TXNRD2 DELAYS THE ANGIOGENIC SWITCH 101
3.3.6. INVESTIGATION OF ANGIOGENIC KEY PLAYERS IN TXNRD2-DEFICIENT
TUMOURS 105
3.3.7. STARVED TXNRD2-DEFICIENT CELLS EXPRESS DECREASED HIF-1 A LEVELS
108
3.3.8. HIF-1A TRANSLATION IS ALTERED IN TXNRD2-DEFICIENT CELLS 110
3.3.9. TXNRD2-NULL TUMOURS ARE SUSCEPTIBLE TO PHARMACOLOGICAL
GSH-INHIBITION 111
3.4. TXNRD2-DEFICIENCY MODIFIES FUNCTION OF ENDOTHELIAL CELLS 114
3.4.1. GENERATION AND CHARACTERISATION OF TXNRD2-DEFICIENT EEPCS 114
3.4.2. TAMOXIFEN-INDUCIBLE ENDOTHELIAL-SPECIFIC TXNRD2 KNOCKOUT MICE 117
4. DISCUSSION 119
4.1. IMMORTALISED MEFS COMPENSATE TXNRD2-DEFICIENCY BY INDUCTION OF
OTHER REDOX-REGULATING ENZYMES 119
4.2. TXNRD2-DEFICIENT FIBROBLASTS SWITCH THEIR ENERGY METABOLISM FROM
OXIDATIVE PHOSPHORYLATION TO ANAEROBIC GLYCOLYSIS 121
4.3. TXNRD2 IS NECESSARY FOR COLONIGENIC POTENTIAL OF TRANSFORMED MEFS
126
4.4. TRANSFORMED TXNRD2-DEFICIENT SINGLE CELL-DERIVED CELLS WERE STILL
SENSITIVE TOWARDS GSH-DEPLETION 128
IMAGE 3
ILL
4.5. LOSS OF TXNRD2 IMPAIRS TUMOUR GROWTH DUE TO LIMITED PROLIFERATION
AND DIMINISHED TUMOUR VASCULARISATION 131
4.6. ANGIOGENIC SIGNALLING IS IMPAIRED IN TXNRD2-DEFICIENT TUMOURS AND
TUMOUR CELLS 133
4.7. DEPLETION OF GSH DE NOVO SYNTHESIS IN TXNRD2-NULL TUMOURS FURTHER
DIMINISHES TUMOUR GROWTH 134
4.8. TXNRD2 IMPACTS ON EEPC PROLIFERATION AND ANGIOGENIC FUNCTION 135
4.9. FUTURE PROSPECTS 137
5. SUMMARY 139
6. REFERENCES 140
7. APPENDIX 172
7.1. ABBREVIATIONS 172
7.2. PUBLICATIONS 178
7.2.1. POSTER PRESENTATIONS 178
7.2.2. ORAL COMMUNICATION 178
7.2.3. ORIGINAL PUBLICATION 179
7.3. CURRICULUM VITAE 180
7.4. ACKNOWLEDGEMENTS 181
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| language | English |
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| physical | VI, 182 S. Ill., graph. Darst. |
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| spelling | Hellfritsch, Juliane Verfasser aut Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth Juliane Hellfritsch 2011 VI, 182 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier München, Univ., Diss., 2011 (DE-588)4113937-9 Hochschulschrift gnd-content Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:19-154659 http://edoc.ub.uni-muenchen.de/15465/ Verlag kostenfrei Volltext https://nbn-resolving.org/urn:nbn:de:bvb:19-154659 Resolving-System DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=025876299&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Hellfritsch, Juliane Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth |
| subject_GND | (DE-588)4113937-9 |
| title | Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth |
| title_auth | Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth |
| title_exact_search | Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth |
| title_full | Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth Juliane Hellfritsch |
| title_fullStr | Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth Juliane Hellfritsch |
| title_full_unstemmed | Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth Juliane Hellfritsch |
| title_short | Loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth |
| title_sort | loss of mitochondrial thioredoxin reductase delays angiogenic switch and impairs tumour growth |
| topic_facet | Hochschulschrift |
| url | http://edoc.ub.uni-muenchen.de/15465/ https://nbn-resolving.org/urn:nbn:de:bvb:19-154659 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=025876299&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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