Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling:
Gespeichert in:
| 1. Verfasser: | |
|---|---|
| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
Berlin
Logos Verl.
2014
|
| Schlagworte: | |
| Online-Zugang: | Inhaltstext Inhaltsverzeichnis |
| Beschreibung: | 213 S. Ill., graph. Darst. |
| ISBN: | 9783832537326 3832537325 |
Internformat
MARC
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| 245 | 1 | 0 | |a Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling |c von Uwe Benary |
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Datensatz im Suchindex
| _version_ | 1809769994724048896 |
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CONTENTS
ZUSAMMENFASSUNG 3
ABSTRACT 7
CONTENTS 11
ABBREVIATIONS 17
1. INTRODUCTION TO THE BIOLOGICAL SCOPE OF THE THESIS 21
1.1 THE UBIQUITIN/PROTEASOME SYSTEM 21
1.1.1 THE PROCESS OF UBIQUITINATION 22
1.1.2 UBIQUITIN-DEPENDENT PROTEOLYSIS BY THE PROTEASOME 24
1.1.3 FUNCTIONS OF UBIQUITIN IN ADDITION TO PROTEIN DEGRADATION 25
1.2 THE WNT/P-CATENIN SIGNALLING PATHWAY 25
1.3 THE CANONICAL NF-KB SIGNALLING PATHWAY 28
1.4 THE P-TRANSDUCIN REPEAT-CONTAINING PROTEIN FAMILY 30
1.4.1 P-TRCP IS A SUBUNIT OF THE SKP-CULLIN-F-BOX UBIQUITIN LIGASE
COMPLEX. 30
1.4.2 THE PARALOGUES P-TRCPL/FWDL AND P-TRCP2/HOS 31
1.5 RESEARCH OBJECTIVES 33
1.5.1 WHAT EFFECTS MAY TRANSCRIPTIONAL REGULATION OF P-TRCP ABUNDANCE
HAVE ON NF-KB DYNAMICS? 35
1.5.2 ARE THE TWO PARALOGUES OF P-TRCP FUNCTIONALLY REDUNDANT IN THE
WNT/P-CATENIN SIGNALLING PATHWAY? 35
1.5.3 UNDER WHAT CONDITIONS WOULD CROSSTALK VIA COMPETITIVE P-TRCP
SEQUESTRATION YIELD OBSERVABLE EFFECTS ON P-CATENIN AND/OR NF-KB
DYNAMICS? 36
2. MATHEMATICAL MODELLING APPROACHES 39
2.1 THE DETAILED KINETIC MODEL OF CANONICAL NF-KB SIGNALLING 40
2.2 THE DETAILED MODEL OF WNT/P-CATENIN SIGNALLING 42
2.3 SIMULATION OF WNT/P-CATENIN SIGNALLING IN CANCER CELLS 44
2.4 DEFINITION OF SIGNALLING TIME, SIGNAL DURATION, AND SIGNAL AMPLITUDE
44
2.5 DEFINITION OF A MEASURE TO QUANTIFY CROSSTALK IMPACT IN TRANSIENT
DYNAMICS 46
2.6 CALCULATION OF SENSITIVITY COEFFICIENTS 47
2.7 BIFURCATION ANALYSIS 48
2.8 KENDALL RANK CORRELATION 49
3. INVESTIGATION OF THE IMPACT OF TRANSCRIPTIONAL REGULATION OF P-TRCP
ABUNDANCE ON
CANONICAL NF-KB SIGNALLING 51
3.1 MODIFICATION OF THE DETAILED MODEL OF CANONICAL NF-KB SIGNALLING 51
3.2 ANALYSIS OF THE MODEL OF CANONICAL NF-KB SIGNALLING 53
HTTP://D-NB.INFO/1052553052
3.2.1 A REDUCTION OF THE VALUE OF KP.RRCP CHANGES SENSITIVITY
COEFFICIENTS OF
NUCLEAR NF-KB 53
3.2.2 THE VALUE OF KP.-IVCP INFLUENCES THE STEADY STATE OF NUCLEAR NF-KB
UPON
TNF STIMULATION 55
3.2.3 THE VALUE OF KP-TICP INFLUENCES SIGNAL AMPLITUDE AND SIGNALLING
TIME OF
NUCLEAR NF-KB DYNAMICS IN RESPONSE TO TNF STIMULATION 56
3.3 DISCUSSION 58
4. DISSECTION OF THE DIFFERENTIAL IMPACT OF FWD1 AND HOS FEEDBACK ON
WNT/P-CATENIN SIGNALLING 65
4.1 DERIVATION OF A WNT/P-CATENIN PATHWAY MODEL INCLUDING THE FWD1 AND
HOS
FEEDBACKS 65
4.1.1 STRUCTURE OF THE TWO-FEEDBACK MODEL 66
4.1.2 RATE KINETICS OF THE TWO-FEEDBACK MODEL 68
4.1.3 DEFINITION OF FEEDBACK STRENGTH 68
4.1.4 PARAMETERISATION 70
4.1.5 PATHWAY STIMULATION BY WNT 72
4.2 ANALYSIS OF THE IMPACT OF THE MODIFICATIONS AND EXTENSIONS IN THE
TWO-FEEDBACK MODEL 73
4.2.1 COMPARISON OF DYNAMICAL FEATURES OF THE TWO-FEEDBACK MODEL AND THE
ORIGINAL DETAILED MODEL OF WNT/P-CATENIN SIGNALLING 73
4.2.2 COMPARISON OF THE UNSTIMULATED STEADY STATE CONCENTRATIONS OF FWD1
AND HOS UNDER WILD TYPE AND APC MUTANT CONDITIONS 74
4.2.3 VARIATION OF FEEDBACK STRENGTH ALLOWS FOR FEEDBACK-SPECIFIC
MODULATION OF HOS OR FWD1 EXPRESSION 75
4.3 ANALYSIS OF THE TWO-FEEDBACK MODEL 77
4.3.1 HOS FEEDBACK STRENGTH MODULATES THE STEADY STATE CONCENTRATION OF
THE P-CATENIN/TCF COMPLEX 77
4.3.2 HOS FEEDBACK STRENGTH INFLUENCES THE DYNAMICS OF THE P-CATENIN/TCF
COMPLEX IN RESPONSE TO TRANSIENT WNT STIMULATION 78
4.3.3 FWD1 FEEDBACK STRENGTH DOES NOT AFFECT THE DYNAMICS OF THE
P-CATENIN/TCF COMPLEX FOR THE REPORTED HOS EXPRESSION LEVEL 79
4.3.4 FWD1 FEEDBACK STRENGTH INFLUENCES THE STEADY STATE CONCENTRATION
OF
THE P-CATENIN/TCF COMPLEX IN THE ABSENCE OF HOS 81
4.3.5 CHANGES IN THE FWD1 OR HOS EXPRESSION LEVEL MODULATE THE
INFLUENCE OF THE HOS FEEDBACK ON THE P-CATENIN/TCF DYNAMICS 82
4.3.6 THE FWD1 FEEDBACK MECHANISM DOES NOT PROTECT AGAINST MUTATIONS
OF APC 83
4.4 DISCUSSION 85
5. EXPLORATION OF THE POTENTIALS OR CROSSTALK BETWEEN THE WNT/P-CATENIN
AND
CANONICAL NF-KB SIGNALLING VIA COMPETITIVE P-TRCP SEQUESTRATION 89
5.1 DEVELOPMENT OF A MINIMAL MODEL OF COMPETITIVE P-TRCP SEQUESTRATION
90
5.1.1 STRUCTURE OF THE MODEL 90
5.1.2 KINETICS USED IN THE MINIMAL MODEL 91
5.2 PARAMETERISATION OF THE MINIMAL MODEL OF COMPETITIVE P-TRCP
SEQUESTRATION 91
5.2.1 GENERATION OF DATA SETS DESCRIBING THE DYNAMICS OF SELECTED
PATHWAY
COMPONENTS 92
5.2.2 MODELLING THE TRANSIENT WNT AND TRANSIENT TNF STIMULUS OF THE
MINIMAL MODEL 93
5.2.3 ESTIMATION OF PARAMETERS OF THE WNT/P-CATENIN SIGNALLING MODULE 96
5.2.4 ESTIMATION OF PARAMETERS IN THE CANONICAL NF-KB SIGNALLING MODULE
98
5.2.5 DESCRIPTION OF THE 400 SELECTED PARAMETER SETS 98
5.3 ANALYSIS OF THE MINIMAL MODEL OF COMPETITIVE P-TRCP SEQUESTRATION
103
5.3.1 STEADY STATES OF P-CATENIN AND NF-KB DO NOT INFLUENCE EACH OTHER
103
5.3.2 MODULATION OF P-TRCP ABUNDANCE REGULATES THE STIMULATED STEADY
STATE
CONCENTRATIONS OF P-CATENIN AND NF-KB IN OPPOSITE DIRECTIONS 104
5.3.3 IMPACT OF PARAMETER VALUES ON THE STIMULATED STEADY STATE
CONCENTRATION RANGES OF NF-KB AND P-CATENIN 106
5.3.4 TNF STIMULATION CAN INFLUENCE WNT/P-CATENIN SIGNAL TRANSDUCTION
112
5.3.5 INFLUENCE OF PARAMETER CHOICE ON CROSSTALK OF TNF TO WNT/P-CATENIN
SIGNALLING 116
5.3.6 EFFECTS OF THE REDUCTION OF PRODUCTION AND DEGRADATION RATES OF
P-TRCP
ON THE IMPACT OF TNF STIMULATION ON WNT/P-CATENIN SIGNALLING 118
5.4 DISCUSSION 123
5.5 PRELIMINARY RESULTS: CONDITIONS THAT INFLUENCE THE DIRECTION OF
CROSSTALK
BETWEEN CANONICAL NF-KB AND WNT/P-CATENIN SIGNALLING 127
5.5.1 INTRODUCTION 127
5.5.2 EFFECTS OF VARIATIONS IN SIGNALLING TIME ON THE DIRECTION OF
CROSSTALK 128
5.5.3 EFFECTS OF SCALING THE RELATIVE CONCENTRATIONS OF THE PATHWAY
COMPONENTS ON THE DIRECTION OF CROSSTALK 130
5.5.4 DISCUSSION 132
6. CONCLUSIONS AND OUTLOOK 135
6.1 SUMMARY 135
6.1.1 ABUNDANCE OF HOS AND FWDI INFLUENCE THE IMPACT OF REGULATORY
FEEDBACKS IN WNT/P-CATENIN SIGNALLING 138
6.1.2 ABUNDANCE OF HOS AND FWD 1 INFLUENCE THE IMPACT OF TRANSCRIPTIONAL
CROSSTALK FROM WNT/P-CATENIN TO CANONICAL NF-KB SIGNALLING 139
6.1.3 REGULATION OF PROTEIN ABUNDANCE IN THE CANONICAL NF-KB AND
WNT/P-CATENIN SIGNALLING PATHWAY MAY INFLUENCE THEIR CROSSTALK 139
6.1.4 MODULATION OF P-TRCP ABUNDANCE TO REGULATE SCF
P
"
I,CP
COMPLEX
ACTIVITY 141
6.2 P-TRCP - A PROMISING PHARMACEUTICAL TARGET? 142
6.3 OUTLOOK ON FUTURE INVESTIGATIONS 144
6.3.1 ADDITIONAL ASPECTS CONNECTED TO P-TRCP IN WNT/P-CATENIN AND NF-KB
SIGNALLING 145
6.3.2 ADDITIONAL POTENTIAL MECHANISMS OF CROSSTALK BETWEEN WNT/P-CATENIN
AND NF-KB SIGNALLING 146
APPENDIX 149
7. MATHEMATICAL MODELS 149
7.1 THE DETAILED KINETIC MODEL OF CANONICAL NF-KB SIGNALLING 149
7.1.1 DIFFERENTIAL EQUATIONS 149
7.1.2 CONSERVATION RELATION 150
7.1.3 RATE EQUATIONS 150
7.1.4 STIMULATION BY TNF 151
7.1.5 MODEL PARAMETERS 152
7.2 THE DETAILED MODEL OF WNT/P-CATENIN SIGNALLING 154
7.2.1 DIFFERENTIAL EQUATIONS 154
7.2.2 CONSERVATION RELATIONS 155
7.2.3 BINDING EQUILIBRIA 155
7.2.4 RATE EQUATIONS 155
7.2.5 STIMULATION BY WNT 156
7.2.6 MODEL PARAMETERS 157
7.3 THE TWO-FEEDBACK MODEL OF WNT/P-CATENIN SIGNALLING INCLUDING THE
FWD1
AND HOS FEEDBACK 159
7.3.1 DIFFERENTIAL EQUATIONS 159
7.3.2 CONSERVATION RELATIONS 160
7.3.3 RATE EQUATIONS 161
7.3.4 STIMULATION BY WNT 162
7.3.5 MODEL PARAMETERS 163
7.4 THE MINIMAL MODEL OF COMPETITIVE P-TRCP SEQUESTRATION 167
7.4.1 DIFFERENTIAL EQUATIONS 167
7.4.2 CONSERVATION RELATION 168
7.4.3 RATE EQUATIONS 168
7.4.4 MODEL PARAMETERS 169
7.4.5 EQUATIONS AND PARAMETERS REGARDING WNT AND TNF STIMULATION 170
8. ADDITIONAL ANALYSES OF THE TWO-FEEDBACK MODEL 173
8.1 NUMBER AND STABILITY OF STEADY STATES 173
8.2 ANALYSIS OF THE LIMIT CYCLE OSCILLATIONS 176
9. ADDITIONAL ANALYSES OF THE MINIMAL MODEL OF COMPETITIVE P-TRCP
SEQUESTRATION 179
9.1 STEADY STATE ANALYSIS OF THE MINIMAL MODEL OF COMPETITIVE P-TRCP
SEQUESTRATION 179
9.2 DERIVATION OF PARAMETER SETS RESCALED IN TIME 183
9.3 DERIVATION OF THE PARAMETER SET RESCALED IN CONCENTRATION 183
9.4 TABLES LISTING KENDALL RANK CORRELATION COEFFICIENTS ANALYSED IN
CHAPTER 5 185
9.5 DYNAMICS OF P-CATENIN CONSIDERING A LONG TIME RANGE 191
LIST OF FIGURES 193
LIST OF TABLES 195
BIBLIOGRAPHY 197
LIST OF PUBLICATIONS 212
ACKNOWLEDGEMENTS,
213 |
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| discipline | Biologie |
| format | Thesis Book |
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| spelling | Benary, Uwe Verfasser (DE-588)1053535872 aut Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling von Uwe Benary Berlin Logos Verl. 2014 213 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Zugl.: Berlin, Humboldt-Universität, Diss., 2014 Wnt-Proteine (DE-588)7515809-7 gnd rswk-swf Mathematisches Modell (DE-588)4114528-8 gnd rswk-swf Signaltransduktion (DE-588)4318717-1 gnd rswk-swf Nuklearfaktor Kappa B (DE-588)4348985-0 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Nuklearfaktor Kappa B (DE-588)4348985-0 s Wnt-Proteine (DE-588)7515809-7 s Signaltransduktion (DE-588)4318717-1 s Mathematisches Modell (DE-588)4114528-8 s DE-604 X:MVB text/html http://deposit.dnb.de/cgi-bin/dokserv?id=4695011&prov=M&dok_var=1&dok_ext=htm Inhaltstext DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027410196&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Benary, Uwe Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling Wnt-Proteine (DE-588)7515809-7 gnd Mathematisches Modell (DE-588)4114528-8 gnd Signaltransduktion (DE-588)4318717-1 gnd Nuklearfaktor Kappa B (DE-588)4348985-0 gnd |
| subject_GND | (DE-588)7515809-7 (DE-588)4114528-8 (DE-588)4318717-1 (DE-588)4348985-0 (DE-588)4113937-9 |
| title | Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling |
| title_auth | Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling |
| title_exact_search | Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling |
| title_full | Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling von Uwe Benary |
| title_fullStr | Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling von Uwe Benary |
| title_full_unstemmed | Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling von Uwe Benary |
| title_short | Mathematical modelling of the beta-TrCP-dependent regulation of canonical NF-kappaB and Wnt/beta-catenin signalling |
| title_sort | mathematical modelling of the beta trcp dependent regulation of canonical nf kappab and wnt beta catenin signalling |
| topic | Wnt-Proteine (DE-588)7515809-7 gnd Mathematisches Modell (DE-588)4114528-8 gnd Signaltransduktion (DE-588)4318717-1 gnd Nuklearfaktor Kappa B (DE-588)4348985-0 gnd |
| topic_facet | Wnt-Proteine Mathematisches Modell Signaltransduktion Nuklearfaktor Kappa B Hochschulschrift |
| url | http://deposit.dnb.de/cgi-bin/dokserv?id=4695011&prov=M&dok_var=1&dok_ext=htm http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027410196&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT benaryuwe mathematicalmodellingofthebetatrcpdependentregulationofcanonicalnfkappabandwntbetacateninsignalling |