Targeting cyclin dependent kinase 5 in hepatocellular carcinoma: a novel therapeutic approach
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| 1. Verfasser: | |
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| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
2014
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| Schlagworte: | |
| Online-Zugang: | kostenfrei http://d-nb.info/1055913947/34 Inhaltsverzeichnis |
| Beschreibung: | 81 S. Ill., graph. Darst. |
| Format: | Langzeitarchivierung gewährleistet, LZA |
Internformat
MARC
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Datensatz im Suchindex
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|---|---|
| adam_text | DISSERTATION ZUR ERLANGUNG DES DOKTORGRADES
DER FAKULTAT FUR CHEMIE UND PHARMAZIE
DER LUDWIG-MAXIMILIANS-UNIVERSITST MUNCHEN
TARGETING CYCLIN DEPENDENT KINASE 5
IN HEPATOCELLULAR CARCINOMA
A NOVEL THERAPEUTIC APPROACH
SANDRA MONIKA EHRLICH
(GEB. STAMM)
AUS EBERSBERG, DEUTSCHLAND
2014
HTTP://D-NB.INFO/1058423096
CONTENTS
5
CONTENTS
1 INTRODUCTION 10
1.1 HEPATOCELLULAR CARCINOMA 10
1.2 CYCLIN DEPENDENT KINASE 5 10
1.2.1 REGULATION OF CDK5 11
1.2.2 FUNCTION OF CDK5 IN THE NERVOUS SYSTEM 12
1.2.3 FUNCTION OF CDK5 IN CANCER 13
1.2.4 PHARMACEUTICAL INHIBITION OF CDK5 13
1.3 AIM OF THE STUDY 14
2 MATERIALS AND METHODS 16
2.1 MATERIALS 16
2.1.1 COMPOUNDS 16
2.1.2 REAGENTS AND TECHNICAL EQUIPMENT 16
2.2 CELL CULTURE 18
2.2.1 SOLUTIONS AND REAGENTS 18
2.2.2 CELL LINES 19
2.2.3 PASSAGING 19
2.2.4 FREEZING AND THAWING 19
2.3 TRANSFECTION EXPERIMENTS 20
2.3.1 CDK5 AND P27
KIP1
SIRNA 20
2.3.2 CDK5 SHRNA 20
2.4 WESTERN BLOT ANALYSIS 21
2.5 NUCLEAR/CYTOPLASMIC FRACTIONATION 23
2.6 IMMUNOPRECIPITATION 24
CONTENTS 6
2.7 KINASE ACTIVITY ASSAY 24
2.8 HUMAN HOC MICROARRAYS 25
2.9 IMMUNOHISTOCHEMISTRY 25
2.9.1 CDK5 AND KI-67 25
2.9.2 TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE DUTP NICK END LABELING
(TUNEL) 26
2.10 IMMUNOSTAINING 26
2.11 PROLIFERATION ASSAYS 27
2.11.1 CRYSTAL VIOLET STAINING 27
2.11.2 IMPEDANCE MEASUREMENT 27
2.12 COLONY FORMATION ASSAY 28
2.13 MOTILITY ASSAYS 28
2.13.1 BOYDEN CHAMBER ASSAY 28
2.13.2 WOUND HEALING ASSAY 28
2.14 CELL CYCLE AND APOPTOSIS ANALYSIS 29
2.15 IN VIVO ASSAYS 30
2.15.1 ANIMALS 30
2.15.2 TUMOR CELL IMPLANTATION 31
2.15.3 INTRAPERITONEAL APPLICATION OF ROSCOVITINE AND IRINOTECAN 31
2.15.4 ISOLATION OF TUMORS 31
2.16 STATISTICAL ANALYSIS 31
3 RESULTS 33
3.1 CDK5 EXPRESSION IS INCREASED IN HUMAN HCC 33
3.2 ABROGATION OF CDK5 INHIBITS HCC PROGRESSION IN VITRO
AND IN VIVO 35
CONTENTS
7
3.2.1 BLOCKAGE OF CDK5 FUNCTION INHIBITS HCC CELL GROWTH AND
MOTILITY IN VITRO 35
3.2.2 INHIBITION OF CDK5 REDUCES HCC TUMOR GROWTH IN A XENOGRAFT
MOUSE MODEL 40
3.3 FUNCTION OF CDK5 IN THE NUCLEUS OF HCC CELLS 42
3.3.1 CDK5 IS LOCALIZED IN THE NUCLEUS OF PROLIFERATING HCC CELLS 42
3.3.2 CDK5 IS ACTIVATED IN THE NUCLEUS OF CELLS IN THE G2/M CELL CYCLE
PHASE 44
3.3.3 CDK5 GETS ACTIVATED BY DNA DAMAGE AND IS INVOLVED IN DNA
DAMAGE RESPONSE 46
3.3.4 CDK5 INFLUENCES DNA DAMAGE CHECKPOINT REGULATION 48
3.3.5 CDK5 IS IMPORTANT FOR ATM PHOSPHORYLATION 50
3.4 CDK5 INHIBITION CHEMOSENSITIZES HCC CELLS FOR
TREATMENT WITH DNA DAMAGE CHEMOTHERAPEUTICS 52
3.5 CDK5 INHIBITION ENHANCES EFFICACY OF SORAFENIB
TREATMENT IN HCC CELLS 56
3.5.1 CDK5 INHIBITION ACTS SYNERGISTIC WITH SORAFENIB ON HCC TUMOR
GROWTH 56
3.5.2 INHIBITION OF CDK5 PREVENTS THE CELL MIGRATION INDUCED BY LOW-
DOSE SORAFENIB 57
4 DISCUSSION 59
4.1 CDK5 IS AN IMPORTANT MEDIATOR IN HCC PROGRESSION 59
4.2 CDK5 REGULATES DNA DAMAGE RESPONSE AND CHECKPOINT
ACTIVATION VIA ATM PATHWAY 60
4.3 COMBINATION OF CDK5 INHIBITION WITH DNA DAMAGE
AGENTS PRESENTS A NOVEL THERAPEUTIC OPTION FOR HCC 62
4.4 CDK5 INHIBITION INCREASES EFFICACY AND RESPONSE TO
SORAFENIB TREATMENT 63
CONTENTS
8
4.5 CDK5 REPRESENTS A NOVEL DRUGABLE TARGET FOR HCC
THERAPY 64
4.6 CONCLUSION AND FURTHER PERSPECTIVES 64
5 SUMMARY 66
6 REFERENCES 68
7 APPENDIX 75
7.1 ABBREVIATIONS 75
7.2 PUBLICATIONS 77
7.2.1 ORIGINAL PUBLICATIONS 77
7.2.2 POSTER PRESENTATIONS 77
7.3 CURRICULUM VITAE 79
7.4 ACKNOWLEDGEMENTS 80
|
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| spelling | Ehrlich, Sandra Monika Verfasser aut Targeting cyclin dependent kinase 5 in hepatocellular carcinoma a novel therapeutic approach Sandra Monika Ehrlich 2014 81 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier München, Univ., Diss., 2014 Langzeitarchivierung gewährleistet, LZA (DE-588)4113937-9 Hochschulschrift gnd-content Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:19-172495 https://nbn-resolving.org/urn:nbn:de:bvb:19-172495 Resolving-System kostenfrei Volltext http://d-nb.info/1055913947/34 Langzeitarchivierung Nationalbibliothek DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027527301&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
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| subject_GND | (DE-588)4113937-9 |
| title | Targeting cyclin dependent kinase 5 in hepatocellular carcinoma a novel therapeutic approach |
| title_auth | Targeting cyclin dependent kinase 5 in hepatocellular carcinoma a novel therapeutic approach |
| title_exact_search | Targeting cyclin dependent kinase 5 in hepatocellular carcinoma a novel therapeutic approach |
| title_full | Targeting cyclin dependent kinase 5 in hepatocellular carcinoma a novel therapeutic approach Sandra Monika Ehrlich |
| title_fullStr | Targeting cyclin dependent kinase 5 in hepatocellular carcinoma a novel therapeutic approach Sandra Monika Ehrlich |
| title_full_unstemmed | Targeting cyclin dependent kinase 5 in hepatocellular carcinoma a novel therapeutic approach Sandra Monika Ehrlich |
| title_short | Targeting cyclin dependent kinase 5 in hepatocellular carcinoma |
| title_sort | targeting cyclin dependent kinase 5 in hepatocellular carcinoma a novel therapeutic approach |
| title_sub | a novel therapeutic approach |
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