Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3:
Gespeichert in:
| 1. Verfasser: | |
|---|---|
| Format: | Buch |
| Sprache: | English |
| Veröffentlicht: |
Karlsruhe
Forschungszentrum Karlsruhe
2005
|
| Ausgabe: | Als Ms. gedr. |
| Schriftenreihe: | Wissenschaftliche Berichte / Forschungszentrum Karlsruhe Technik und Umwelt
7124 |
| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | Zugl.: Karlsruhe, Univ., Diss., 2005 |
| Beschreibung: | XIV, 104 S. Ill., graph. Darst. |
Internformat
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| 490 | 1 | |a Wissenschaftliche Berichte / Forschungszentrum Karlsruhe Technik und Umwelt |v 7124 | |
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Datensatz im Suchindex
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|---|---|
| adam_text | TABLE OF CONTENTS
Zusammenfassung i
Abstract ii
Acknowledgements iii
Table of contents v
List of figures ix
List of tables x
Abbreviations xi
1. INTRODUCTION 1
1.1. The p53 tumor suppressor protein 2
1.1.1 Transcriptional activation function of the p53 protein 2
1.1.2 P53, direct activator of apoptosis 3
1.1.3 Structure of the p53 protein 3
1.1.4 P53 is degraded via the ubiquitin dependent proteasome degradation 4
1.2 General principles of ubiquitylation dependent proteasomal degradation. 4
1.3 The p53 degradation pathway 6
1.3.1 The Mdm2 protein is a major negative regulator of p53. 7
1.3.1.1 The interaction of Mdm2 and p53 is a prerequisite for p53
ubiquitylation and degradation. 8
1.3.1.2 Co localization of p53 and Mdm2 is a prerequisite for Mdm2
mediated degradation of the p53 protein 10
1.3.1.3 Ubiquitylation of the p53 protein is tightly regulated 12
1.3.1.3.1 The Mdm2 ubiquitin ligase activity is regulated by protein protein
interactions 12
1.3.1.3.2 Non protein ligands change Mdm2 binding specificity 15
1.3.1.3.3 The Mdm2 protein interacts with many proteins that regulate
multiple pathways 15
1.3.1.3.4 Mdm2 functions are regulated by post translational modifications 16
1.3.1.4 hRad23 proteins regulate the post ubiquitylation function of the
Mdm2 protein 18
1.3.2 The central domain of the Mdm2 protein: at the crossroads of p53
ubiquitylation and degradation. 19
1.4 Glycogen Synthase Kinase 3 (GSK 3) 21
V
1.4.1 Regulation of GSK 3 21
1.4.1.1 Regulation of GSK 3 by phosphorylation 21
1.4.1.2 Regulation of the intracellular localization of GSK 3 23
1.4.1.3 Regulation of GSK 3 by binding proteins 23
AIM 24
2. MATERIALS AND METHODS 25
2.1 MATERIALS 25
2.1.1 Chemicals 25
2.1.2 Kits 26
2.1.3 Binding matrices 26
2.1.4 Oligonucleotides 26
2.1.5 Plasmids 28
2.1.6 Antibodies 29
2.1.7 Enzymes 30
2.1.8 Bacteria 31
2.1.9 Cell lines and media 31
2.1.10 Other materials 31
2.2 METHODS 32
2.2.1 CELL CULTURE AND TRANSFECTION METHODS 32
2.2.1.1 Cell culture 32
2.2.1.2 Freezing and thawing of cells 32
2.2.1.3 Transfection of cells with jet Pei reagent 32
2.2.1.4 Transfection of cells with calcium phosphate 32
2.2.1.5 Magnetic separation of transfected cells 33
2.2.1.6 Treatment of cell lines 33
2.2.2 NUCLEIC ACIDS METHODS 33
2.2.2.1 Determination of nucleic acid concentration 33
2.2.2.2 Plasmid DNA preparation 34
2.2.2.2.1 Large scale plasmid preparation 34
2.2.2.2.2 Small scale plasmid preparation 34
2.2.2.3 Restriction endonuclease digestion of DNA 34
2.2.2.4 Agarose gel electrophoresis 35
vi
2.2.2.5 Isolation/purification of DNA from agarose gels 35
2.2.2.6 DNA ligation 35
2.2.2.7 Sub cloning 35
2.2.2.8 Polymerase Chain Reaction (PCR) 35
2.2.2.9 Cloning into pCR® Blunt II TOPO® vector 36
2.2.2.10 Transformation of chemically competent bacteria 36
2.2.2.11 Construction of siRNA expressing plasmids 36
2.2.2.12 Site directed mutagenesis 37
2.2.2.13 Manual (radioactive) DNA sequencing 37
2.2.2.14 Isolation of polyA RNA from cultured cells 37
2.2.2.15 Northern blotting 38
2.2.2.16 Radioactive labelling of cDNAs for Northern hybridization 38
2.2.2.17 Preparation of cDNA 39
2.2.3 PROTEIN METHODS 39
2.2.3.1 Determination of protein concentration 39
2.2.3.2 Preparation of cell lysate 39
2.2.3.3 SDS polyacrylamide gel electrophoresis 40
2.2.3.4 Western Blotting 40
2.2.3.5 Immunoprecipitation 41
2.2.3.6 Ubiquitylation assay 41
2.2.3.7 Preparation of GST fusion proteins 41
2.2.3.8 Kinase assays 42
2.2.3.9 In vivo labelling of cells with 32P orthophosphate 43
2.2.3.10 Two dimensional peptide mapping 43
2.2.3.11 Immunofluorescence staining 44
3. RESULTS 45
3.1. GSK 3 phosphorylates Mdm2 in vitro and in vivo 45
3.2 Inhibition of GSK 3 leads to p53 accumulation 53
3.3 Accumulated p53 is transcriptionally active 55
3.4 GSK 3 regulates p53 degradation 56
3.5 Inhibition of GSK 3 does not interfere with p53 ubiquitylation 61
3.6 GSK 3 regulates the Mdm2 proteasome interaction 67
vii
3.7 Mutants of Mdm2 where GSK 3 consensus sites are mutated into alanine
ubiquitylate p53 but do not promote p53 degradation 68
3.8 GSK 3 is inhibited after ionizing irradiation 70
3.9 Inactivation of GSK 3 contributes to p53 accumulation after IR 72
4. DISCUSSION 75
4.1 The Mdm2 protein is a physiological substrate for GSK 3 75
4.2 Phosphorylation of the central region of the Mdm2 protein regulates its
interaction with the proteasome. 81
4.3 The accumulation of ubiquitylated p53 leads to selective activation of
p21/waf 1 and mdm2 transcription 83
4.4 GSK 3 contributes to the activation of the p53 protein in response to DNA
damage 84
4.5 Model of p53 regulation by GSK 3: conclusion 86
5. REFERENCES 89
iix
LIST OF FIGURES
Figure 1.1. The p53 protein is at the crossroads of multiple cellular stress
pathways. 2
Figure 1.2. The ubiquitylation dependent proteasomal degradation pathway. 5
Figure 1.3. Functional domains of the Mdm2 protein. 7
Figure 1.4. Schematic representation of p53 degradation pathway. 9
Figure 1.5. Topology of p53 ubiquitylation. 11
Figure 1.6. Regulation of p53 ubiquitylation. 13
Figure 1.7. Mdm2 interacting proteins. 13
Figure 1.8. Posttranslational modifications of Mdm2. 17
Figure 1.9. Regulation of glycogen synthase kinase 3 (GSK 3) by
phosphorylation. 22
Figure 2.1. Design of oligonucleotides for generating siRNA expressing
plasmids. 36
Figure 3.1. GSK3 consensus sites in the central domain of Mdm2. 45
Figure 3.2. GSK 3p phosphorylates Mdm2 in vitro. 46
Figure 3.3. Phosphorylation of Mdm2 by GSK 3p is enhanced after priming by
CKIS. 48
Figure 3.4. Two dimensional peptide map of Mdm2 phosphorylated in vivo. 50
Figure 3.5. GSK 3 phosphorylates Mdm2 in vivo. 51
Figure 3.6. Mdm2 interacts with GSK 3|3. 52
Figure 3.7. Inhibition of GSK 3 leads to the accumulation of p53. 54
Figure 3.8. GSK 3 inhibition leads to the accumulation of transcriptionally active
p53. 56
Figure 3.9. Inhibition of GSK 3 prevents p53 degradation I. 57
Figure 3.10. Inhibition of GSK 3 prevents p53 degradation II. 59
Figure 3.11. Accumulation of p53 after GSK 3 inhibition depends on the presence
of Mdm2. 60
Figure 3.12. Inhibition of GSK 3 leads to the accumulation of E2F 1. 61
Figure 3.13. p53 is not phosphorylated by GSK 3. 62
Figure 3.14. GSK 3 inhibition does not change the intracellular localization of p53
and Mdm2. 63
Figure 3.15. GSK 3 inhibition does not influence p53 Mdm2 interaction. 64
Figure 3.16. GSK 3 inhibition does not influence Mdm2/MdmX interaction. 65
Figure 3.17. GSK 3 inhibition does not change p53 ubiquitylation. 67
ix
Figure 3.18. GSK 3 inhibition blocks the interaction of the Mdm2 protein with
the proteasome. 68
Figure 3.19. Hypophosphorylated Mdm2 doesn t degrade p53. 69
Figure 3.20. GSK 3p is inactivated towards primed substrates after ionizing
irradiation. 71
Figure 3.21. Expression of a constitutive active GSK 3 mutant reduces p53
accumulation after ionizing irradiation. 73
Figure 4.1. Model of p53 regulation by GSK 3. 87
LIST OF TABLES
Table 4.1. Criteria for identifying physiological substrates of GSK 3. 79
x
|
| adam_txt |
TABLE OF CONTENTS
Zusammenfassung i
Abstract ii
Acknowledgements iii
Table of contents v
List of figures ix
List of tables x
Abbreviations xi
1. INTRODUCTION 1
1.1. The p53 tumor suppressor protein 2
1.1.1 Transcriptional activation function of the p53 protein 2
1.1.2 P53, direct activator of apoptosis 3
1.1.3 Structure of the p53 protein 3
1.1.4 P53 is degraded via the ubiquitin dependent proteasome degradation 4
1.2 General principles of ubiquitylation dependent proteasomal degradation. 4
1.3 The p53 degradation pathway 6
1.3.1 The Mdm2 protein is a major negative regulator of p53. 7
1.3.1.1 The interaction of Mdm2 and p53 is a prerequisite for p53
ubiquitylation and degradation. 8
1.3.1.2 Co localization of p53 and Mdm2 is a prerequisite for Mdm2
mediated degradation of the p53 protein 10
1.3.1.3 Ubiquitylation of the p53 protein is tightly regulated 12
1.3.1.3.1 The Mdm2 ubiquitin ligase activity is regulated by protein protein
interactions 12
1.3.1.3.2 Non protein ligands change Mdm2 binding specificity 15
1.3.1.3.3 The Mdm2 protein interacts with many proteins that regulate
multiple pathways 15
1.3.1.3.4 Mdm2 functions are regulated by post translational modifications 16
1.3.1.4 hRad23 proteins regulate the post ubiquitylation function of the
Mdm2 protein 18
1.3.2 The central domain of the Mdm2 protein: at the crossroads of p53
ubiquitylation and degradation. 19
1.4 Glycogen Synthase Kinase 3 (GSK 3) 21
V
1.4.1 Regulation of GSK 3 21
1.4.1.1 Regulation of GSK 3 by phosphorylation 21
1.4.1.2 Regulation of the intracellular localization of GSK 3 23
1.4.1.3 Regulation of GSK 3 by binding proteins 23
AIM 24
2. MATERIALS AND METHODS 25
2.1 MATERIALS 25
2.1.1 Chemicals 25
2.1.2 Kits 26
2.1.3 Binding matrices 26
2.1.4 Oligonucleotides 26
2.1.5 Plasmids 28
2.1.6 Antibodies 29
2.1.7 Enzymes 30
2.1.8 Bacteria 31
2.1.9 Cell lines and media 31
2.1.10 Other materials 31
2.2 METHODS 32
2.2.1 CELL CULTURE AND TRANSFECTION METHODS 32
2.2.1.1 Cell culture 32
2.2.1.2 Freezing and thawing of cells 32
2.2.1.3 Transfection of cells with jet Pei reagent 32
2.2.1.4 Transfection of cells with calcium phosphate 32
2.2.1.5 Magnetic separation of transfected cells 33
2.2.1.6 Treatment of cell lines 33
2.2.2 NUCLEIC ACIDS METHODS 33
2.2.2.1 Determination of nucleic acid concentration 33
2.2.2.2 Plasmid DNA preparation 34
2.2.2.2.1 Large scale plasmid preparation 34
2.2.2.2.2 Small scale plasmid preparation 34
2.2.2.3 Restriction endonuclease digestion of DNA 34
2.2.2.4 Agarose gel electrophoresis 35
vi
2.2.2.5 Isolation/purification of DNA from agarose gels 35
2.2.2.6 DNA ligation 35
2.2.2.7 Sub cloning 35
2.2.2.8 Polymerase Chain Reaction (PCR) 35
2.2.2.9 Cloning into pCR® Blunt II TOPO® vector 36
2.2.2.10 Transformation of chemically competent bacteria 36
2.2.2.11 Construction of siRNA expressing plasmids 36
2.2.2.12 Site directed mutagenesis 37
2.2.2.13 Manual (radioactive) DNA sequencing 37
2.2.2.14 Isolation of polyA RNA from cultured cells 37
2.2.2.15 Northern blotting 38
2.2.2.16 Radioactive labelling of cDNAs for Northern hybridization 38
2.2.2.17 Preparation of cDNA 39
2.2.3 PROTEIN METHODS 39
2.2.3.1 Determination of protein concentration 39
2.2.3.2 Preparation of cell lysate 39
2.2.3.3 SDS polyacrylamide gel electrophoresis 40
2.2.3.4 Western Blotting 40
2.2.3.5 Immunoprecipitation 41
2.2.3.6 Ubiquitylation assay 41
2.2.3.7 Preparation of GST fusion proteins 41
2.2.3.8 Kinase assays 42
2.2.3.9 In vivo labelling of cells with 32P orthophosphate 43
2.2.3.10 Two dimensional peptide mapping 43
2.2.3.11 Immunofluorescence staining 44
3. RESULTS 45
3.1. GSK 3 phosphorylates Mdm2 in vitro and in vivo 45
3.2 Inhibition of GSK 3 leads to p53 accumulation 53
3.3 Accumulated p53 is transcriptionally active 55
3.4 GSK 3 regulates p53 degradation 56
3.5 Inhibition of GSK 3 does not interfere with p53 ubiquitylation 61
3.6 GSK 3 regulates the Mdm2 proteasome interaction 67
vii
3.7 Mutants of Mdm2 where GSK 3 consensus sites are mutated into alanine
ubiquitylate p53 but do not promote p53 degradation 68
3.8 GSK 3 is inhibited after ionizing irradiation 70
3.9 Inactivation of GSK 3 contributes to p53 accumulation after IR 72
4. DISCUSSION 75
4.1 The Mdm2 protein is a physiological substrate for GSK 3 75
4.2 Phosphorylation of the central region of the Mdm2 protein regulates its
interaction with the proteasome. 81
4.3 The accumulation of ubiquitylated p53 leads to selective activation of
p21/waf 1 and mdm2 transcription 83
4.4 GSK 3 contributes to the activation of the p53 protein in response to DNA
damage 84
4.5 Model of p53 regulation by GSK 3: conclusion 86
5. REFERENCES 89
iix
LIST OF FIGURES
Figure 1.1. The p53 protein is at the crossroads of multiple cellular stress
pathways. 2
Figure 1.2. The ubiquitylation dependent proteasomal degradation pathway. 5
Figure 1.3. Functional domains of the Mdm2 protein. 7
Figure 1.4. Schematic representation of p53 degradation pathway. 9
Figure 1.5. Topology of p53 ubiquitylation. 11
Figure 1.6. Regulation of p53 ubiquitylation. 13
Figure 1.7. Mdm2 interacting proteins. 13
Figure 1.8. Posttranslational modifications of Mdm2. 17
Figure 1.9. Regulation of glycogen synthase kinase 3 (GSK 3) by
phosphorylation. 22
Figure 2.1. Design of oligonucleotides for generating siRNA expressing
plasmids. 36
Figure 3.1. GSK3 consensus sites in the central domain of Mdm2. 45
Figure 3.2. GSK 3p phosphorylates Mdm2 in vitro. 46
Figure 3.3. Phosphorylation of Mdm2 by GSK 3p is enhanced after priming by
CKIS. 48
Figure 3.4. Two dimensional peptide map of Mdm2 phosphorylated in vivo. 50
Figure 3.5. GSK 3 phosphorylates Mdm2 in vivo. 51
Figure 3.6. Mdm2 interacts with GSK 3|3. 52
Figure 3.7. Inhibition of GSK 3 leads to the accumulation of p53. 54
Figure 3.8. GSK 3 inhibition leads to the accumulation of transcriptionally active
p53. 56
Figure 3.9. Inhibition of GSK 3 prevents p53 degradation I. 57
Figure 3.10. Inhibition of GSK 3 prevents p53 degradation II. 59
Figure 3.11. Accumulation of p53 after GSK 3 inhibition depends on the presence
of Mdm2. 60
Figure 3.12. Inhibition of GSK 3 leads to the accumulation of E2F 1. 61
Figure 3.13. p53 is not phosphorylated by GSK 3. 62
Figure 3.14. GSK 3 inhibition does not change the intracellular localization of p53
and Mdm2. 63
Figure 3.15. GSK 3 inhibition does not influence p53 Mdm2 interaction. 64
Figure 3.16. GSK 3 inhibition does not influence Mdm2/MdmX interaction. 65
Figure 3.17. GSK 3 inhibition does not change p53 ubiquitylation. 67
ix
Figure 3.18. GSK 3 inhibition blocks the interaction of the Mdm2 protein with
the proteasome. 68
Figure 3.19. Hypophosphorylated Mdm2 doesn't degrade p53. 69
Figure 3.20. GSK 3p is inactivated towards primed substrates after ionizing
irradiation. 71
Figure 3.21. Expression of a constitutive active GSK 3 mutant reduces p53
accumulation after ionizing irradiation. 73
Figure 4.1. Model of p53 regulation by GSK 3. 87
LIST OF TABLES
Table 4.1. Criteria for identifying physiological substrates of GSK 3. 79
x |
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| id | DE-604.BV020850609 |
| illustrated | Illustrated |
| index_date | 2024-07-02T13:19:41Z |
| indexdate | 2024-07-09T20:26:37Z |
| institution | BVB |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-014172320 |
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| physical | XIV, 104 S. Ill., graph. Darst. |
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| record_format | marc |
| series2 | Wissenschaftliche Berichte / Forschungszentrum Karlsruhe Technik und Umwelt |
| spelling | Kulikov, Roman 1980- Verfasser (DE-588)130357065 aut Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 Roman Kulikov FZKA 7124 Als Ms. gedr. Karlsruhe Forschungszentrum Karlsruhe 2005 XIV, 104 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Wissenschaftliche Berichte / Forschungszentrum Karlsruhe Technik und Umwelt 7124 Zugl.: Karlsruhe, Univ., Diss., 2005 Regulation (DE-588)4049075-0 gnd rswk-swf Protein p53 (DE-588)4176550-3 gnd rswk-swf Glykogensynthase (DE-588)4256835-3 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Protein p53 (DE-588)4176550-3 s Regulation (DE-588)4049075-0 s Glykogensynthase (DE-588)4256835-3 s DE-188 Forschungszentrum Karlsruhe Technik und Umwelt Wissenschaftliche Berichte 7124 (DE-604)BV010181833 7124 HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=014172320&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Kulikov, Roman 1980- Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 Regulation (DE-588)4049075-0 gnd Protein p53 (DE-588)4176550-3 gnd Glykogensynthase (DE-588)4256835-3 gnd |
| subject_GND | (DE-588)4049075-0 (DE-588)4176550-3 (DE-588)4256835-3 (DE-588)4113937-9 |
| title | Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 |
| title_alt | FZKA 7124 |
| title_auth | Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 |
| title_exact_search | Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 |
| title_exact_search_txtP | Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 |
| title_full | Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 Roman Kulikov |
| title_fullStr | Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 Roman Kulikov |
| title_full_unstemmed | Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 Roman Kulikov |
| title_short | Regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 |
| title_sort | regulation of the p53 tumor suppressor protein by glycogen synthase kinase 3 |
| topic | Regulation (DE-588)4049075-0 gnd Protein p53 (DE-588)4176550-3 gnd Glykogensynthase (DE-588)4256835-3 gnd |
| topic_facet | Regulation Protein p53 Glykogensynthase Hochschulschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=014172320&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| volume_link | (DE-604)BV010181833 |
| work_keys_str_mv | AT kulikovroman regulationofthep53tumorsuppressorproteinbyglycogensynthasekinase3 AT kulikovroman fzka7124 |