Samenvatting moleculaire biologie van de cel
Vesiculair transport, cytoskelet, celcyclus, stamcellen, junctions,
metabolisme & kanker
Biomedische Wetenschappen
2020-2021
Door Nicole (studente BMW)
,Inhoudsopgave
Vesiculair transport ................................................................................................................................. 5
Vorming van vesikels ........................................................................................................................... 6
Fosfatidylinositol (PI) ....................................................................................................................... 7
Clathrin-coated vesikels .................................................................................................................. 8
COPII-coated vesikels ...................................................................................................................... 9
Buiging membranen ...................................................................................................................... 10
Afsnoering van vesikels ................................................................................................................. 12
Uncoating ...................................................................................................................................... 12
Transport van vesikels ....................................................................................................................... 13
Rab eiwitten .................................................................................................................................. 14
Fusering van vesikels ......................................................................................................................... 15
Homotypische fusie ....................................................................................................................... 16
Synaptische vesikels ...................................................................................................................... 16
Toxines........................................................................................................................................... 17
Vesiculaire transport pathways ......................................................................................................... 17
COP-coated vesikels ...................................................................................................................... 17
Golgisysteem ................................................................................................................................. 19
Endocytose, fagocytose en autofagie............................................................................................ 24
Exocytose....................................................................................................................................... 29
Cytoskelet .............................................................................................................................................. 30
Actine................................................................................................................................................. 31
Polymerisatie ................................................................................................................................. 32
Microtubuli ........................................................................................................................................ 34
Polymerisatie ................................................................................................................................. 35
Chemische inhibitors ......................................................................................................................... 36
Actine............................................................................................................................................. 36
Microtubuli .................................................................................................................................... 36
Regulatie van de cytoskeletale organisatie (dynamisch) .................................................................. 37
Subunit sekwestratie ..................................................................................................................... 37
Nucleatie........................................................................................................................................ 38
Interactie met uiteinden van filamenten ...................................................................................... 40
Binding en stabilisatie.................................................................................................................... 43
Destabilisatie ................................................................................................................................. 45
Intermediaire filamenten .................................................................................................................. 47
Septines ............................................................................................................................................. 49
1
, Cytoskelet van bacteriën ................................................................................................................... 50
Motoreiwitten ................................................................................................................................... 52
Actine............................................................................................................................................. 52
Microtubuli .................................................................................................................................... 53
Functies motoreiwitten ................................................................................................................. 56
Sliding van cytoskeletale fragmenten ........................................................................................... 57
Cilia en flagella................................................................................................................................... 60
Cel polarisatie en migratie................................................................................................................. 61
Celcyclus ................................................................................................................................................ 65
Mitose................................................................................................................................................ 66
Profase ........................................................................................................................................... 66
Prometafase .................................................................................................................................. 67
Metafase........................................................................................................................................ 68
Anafase .......................................................................................................................................... 68
Telofase ......................................................................................................................................... 69
Cytokinese ......................................................................................................................................... 69
Mitotische spoelfiguren .................................................................................................................... 70
Organisatie .................................................................................................................................... 70
Scheiding van zusterchromatiden tijdens anafase ............................................................................ 73
Cytokinese ......................................................................................................................................... 74
Lokalisatie contractiele ring .......................................................................................................... 76
Regulatie celcyclus ................................................................................................................................ 78
Cycline-Cdk complexen ..................................................................................................................... 80
Regulatie ........................................................................................................................................ 81
Activatie van de celcyclus .................................................................................................................. 88
DNA replicatie.................................................................................................................................... 92
Effecten van Cdks .......................................................................................................................... 94
DNA schade ................................................................................................................................... 98
Mitose vs. meiose I ............................................................................................................................ 99
Overzicht celcyclus controle system ............................................................................................... 100
Stamcellen ........................................................................................................................................... 101
Routes dochtercellen ...................................................................................................................... 102
Vernieuwing darmepitheel.............................................................................................................. 104
Autoradiografie ........................................................................................................................... 105
Stamcel niche .............................................................................................................................. 106
Delta-Notch signalering ............................................................................................................... 108
2
, Vernieuwing van de huid................................................................................................................. 110
Geschiedenis ................................................................................................................................... 111
Hematopoëse .................................................................................................................................. 112
Satellietcellen .................................................................................................................................. 114
Regeneratie zonder stamcellen ........................................................................................................... 115
Modelsystemen ............................................................................................................................... 115
Platwormen ................................................................................................................................. 115
Vertebraten ................................................................................................................................. 117
Weefselkweek ................................................................................................................................. 120
Cell junctions, polariteit en ECM ......................................................................................................... 124
Cell junctions ................................................................................................................................... 124
Tight junctions (occluding junctions)........................................................................................... 125
Zonula adherens (anchoring junctions) ....................................................................................... 125
Desmosomen (anchoring junctions) ........................................................................................... 125
Hemidesmosomen (anchoring junctions) ................................................................................... 125
Gap junctions (channel forming junctions) ................................................................................. 125
Polariteit ...................................................................................................................................... 126
Anchoring junctions......................................................................................................................... 126
Cadherines ................................................................................................................................... 127
Integrines ..................................................................................................................................... 136
Overzicht ..................................................................................................................................... 141
Occluding junctions ......................................................................................................................... 141
Epitheelcellen .............................................................................................................................. 142
Tight junctions ............................................................................................................................. 144
Polariteit .......................................................................................................................................... 145
Madin-Darby Canine Kidney (MDCK) cellen ................................................................................ 145
Eiwitcomplexen ........................................................................................................................... 146
Weefselpolariteit (planar cell polarity) ....................................................................................... 147
Wnt-signalering ........................................................................................................................... 148
Extracellulaire matrix (ECM) ............................................................................................................ 149
Grondsubstantie (tussenstof) ...................................................................................................... 149
Afbraak ECM ................................................................................................................................ 155
Basale lamina................................................................................................................................... 156
Metabolisme ....................................................................................................................................... 158
Fermentatie ..................................................................................................................................... 159
Warburg effect ............................................................................................................................ 160
3
, Mitochondriën ............................................................................................................................. 161
Metabolische drugs ..................................................................................................................... 166
Elektronendragers ....................................................................................................................... 167
Acetyl CoA ....................................................................................................................................... 172
Synthese acetyl CoA .................................................................................................................... 173
Epigenetica .................................................................................................................................. 173
Oorzaak of gevolg ............................................................................................................................ 176
Opname van glucose ................................................................................................................... 177
Vetzuursynthese .......................................................................................................................... 178
Pyruvaat kinasen (PKM1/M2)...................................................................................................... 180
Omzetting van pyruvaat .............................................................................................................. 181
Omgeving......................................................................................................................................... 181
Kanker.................................................................................................................................................. 182
Nomenclatuur.................................................................................................................................. 183
Epitheliale tumoren ..................................................................................................................... 183
Mesenchymale tumoren ............................................................................................................. 184
Uitzonderingen ............................................................................................................................ 185
Incidentie en mortaliteit.................................................................................................................. 185
Tumorgroei ...................................................................................................................................... 187
Genetische afwijkingen ................................................................................................................... 188
Omgeving en leefstijlfactoren ..................................................................................................... 188
Tumorigenese .................................................................................................................................. 189
Metastase ........................................................................................................................................ 192
Hallmarks ......................................................................................................................................... 193
Cancer-critical genes ................................................................................................................... 194
Proto-oncogen ............................................................................................................................. 197
Tumor-suppressor gen ................................................................................................................ 198
Epigenetische inactivatie ............................................................................................................. 199
Herstel DNA schade ..................................................................................................................... 200
Chromosomale afwijkingen ............................................................................................................. 204
Behandeling van kanker .................................................................................................................. 209
Kinasen als drugtargets ............................................................................................................... 210
Organoïden ...................................................................................................................................... 216
Tumor organoïden ....................................................................................................................... 216
Immunotherapie.............................................................................................................................. 222
Voor- en nadelen ......................................................................................................................... 225
4
, Vesiculair transport
Vesiculair transport is noodzakelijk voor het uitwisselen van componenten tussen de verschillende
organellen zonder dat de identiteit van de compartimenten verloren gaat. Hierbij snoeren er vesikels
van de membranen af, die een bepaalde inhoud (cargo) bevatten. Vervolgens fuseren deze vesikels
met het membraan van een ander compartiment, waardoor de inhoud (cargo) aan de cel afgegeven
wordt.
Figuur 1 Schematische weergave van vesiculair transport.
Er zijn verschillende manieren waarop vesiculair transport plaats kan vinden, dit is hieronder
weergegeven in een 'roadmap'. De verschillende transportroutes zijn als volgt:
• Endocytose → Hierbij worden stoffen uit de externe omgeving opgenomen via endosomen.
• Exocytose → Hierbij vindt secretie van stoffen plaats.
• Retrieval → Hierbij worden de lipiden die gebruikt worden voor het vormen van vesikels
terug naar het ER gebracht (gerecycled).
Figuur 2 Schematische weergave van de 'roadmap' van vesiculair transport.
5
Vesiculair transport, cytoskelet, celcyclus, stamcellen, junctions,
metabolisme & kanker
Biomedische Wetenschappen
2020-2021
Door Nicole (studente BMW)
,Inhoudsopgave
Vesiculair transport ................................................................................................................................. 5
Vorming van vesikels ........................................................................................................................... 6
Fosfatidylinositol (PI) ....................................................................................................................... 7
Clathrin-coated vesikels .................................................................................................................. 8
COPII-coated vesikels ...................................................................................................................... 9
Buiging membranen ...................................................................................................................... 10
Afsnoering van vesikels ................................................................................................................. 12
Uncoating ...................................................................................................................................... 12
Transport van vesikels ....................................................................................................................... 13
Rab eiwitten .................................................................................................................................. 14
Fusering van vesikels ......................................................................................................................... 15
Homotypische fusie ....................................................................................................................... 16
Synaptische vesikels ...................................................................................................................... 16
Toxines........................................................................................................................................... 17
Vesiculaire transport pathways ......................................................................................................... 17
COP-coated vesikels ...................................................................................................................... 17
Golgisysteem ................................................................................................................................. 19
Endocytose, fagocytose en autofagie............................................................................................ 24
Exocytose....................................................................................................................................... 29
Cytoskelet .............................................................................................................................................. 30
Actine................................................................................................................................................. 31
Polymerisatie ................................................................................................................................. 32
Microtubuli ........................................................................................................................................ 34
Polymerisatie ................................................................................................................................. 35
Chemische inhibitors ......................................................................................................................... 36
Actine............................................................................................................................................. 36
Microtubuli .................................................................................................................................... 36
Regulatie van de cytoskeletale organisatie (dynamisch) .................................................................. 37
Subunit sekwestratie ..................................................................................................................... 37
Nucleatie........................................................................................................................................ 38
Interactie met uiteinden van filamenten ...................................................................................... 40
Binding en stabilisatie.................................................................................................................... 43
Destabilisatie ................................................................................................................................. 45
Intermediaire filamenten .................................................................................................................. 47
Septines ............................................................................................................................................. 49
1
, Cytoskelet van bacteriën ................................................................................................................... 50
Motoreiwitten ................................................................................................................................... 52
Actine............................................................................................................................................. 52
Microtubuli .................................................................................................................................... 53
Functies motoreiwitten ................................................................................................................. 56
Sliding van cytoskeletale fragmenten ........................................................................................... 57
Cilia en flagella................................................................................................................................... 60
Cel polarisatie en migratie................................................................................................................. 61
Celcyclus ................................................................................................................................................ 65
Mitose................................................................................................................................................ 66
Profase ........................................................................................................................................... 66
Prometafase .................................................................................................................................. 67
Metafase........................................................................................................................................ 68
Anafase .......................................................................................................................................... 68
Telofase ......................................................................................................................................... 69
Cytokinese ......................................................................................................................................... 69
Mitotische spoelfiguren .................................................................................................................... 70
Organisatie .................................................................................................................................... 70
Scheiding van zusterchromatiden tijdens anafase ............................................................................ 73
Cytokinese ......................................................................................................................................... 74
Lokalisatie contractiele ring .......................................................................................................... 76
Regulatie celcyclus ................................................................................................................................ 78
Cycline-Cdk complexen ..................................................................................................................... 80
Regulatie ........................................................................................................................................ 81
Activatie van de celcyclus .................................................................................................................. 88
DNA replicatie.................................................................................................................................... 92
Effecten van Cdks .......................................................................................................................... 94
DNA schade ................................................................................................................................... 98
Mitose vs. meiose I ............................................................................................................................ 99
Overzicht celcyclus controle system ............................................................................................... 100
Stamcellen ........................................................................................................................................... 101
Routes dochtercellen ...................................................................................................................... 102
Vernieuwing darmepitheel.............................................................................................................. 104
Autoradiografie ........................................................................................................................... 105
Stamcel niche .............................................................................................................................. 106
Delta-Notch signalering ............................................................................................................... 108
2
, Vernieuwing van de huid................................................................................................................. 110
Geschiedenis ................................................................................................................................... 111
Hematopoëse .................................................................................................................................. 112
Satellietcellen .................................................................................................................................. 114
Regeneratie zonder stamcellen ........................................................................................................... 115
Modelsystemen ............................................................................................................................... 115
Platwormen ................................................................................................................................. 115
Vertebraten ................................................................................................................................. 117
Weefselkweek ................................................................................................................................. 120
Cell junctions, polariteit en ECM ......................................................................................................... 124
Cell junctions ................................................................................................................................... 124
Tight junctions (occluding junctions)........................................................................................... 125
Zonula adherens (anchoring junctions) ....................................................................................... 125
Desmosomen (anchoring junctions) ........................................................................................... 125
Hemidesmosomen (anchoring junctions) ................................................................................... 125
Gap junctions (channel forming junctions) ................................................................................. 125
Polariteit ...................................................................................................................................... 126
Anchoring junctions......................................................................................................................... 126
Cadherines ................................................................................................................................... 127
Integrines ..................................................................................................................................... 136
Overzicht ..................................................................................................................................... 141
Occluding junctions ......................................................................................................................... 141
Epitheelcellen .............................................................................................................................. 142
Tight junctions ............................................................................................................................. 144
Polariteit .......................................................................................................................................... 145
Madin-Darby Canine Kidney (MDCK) cellen ................................................................................ 145
Eiwitcomplexen ........................................................................................................................... 146
Weefselpolariteit (planar cell polarity) ....................................................................................... 147
Wnt-signalering ........................................................................................................................... 148
Extracellulaire matrix (ECM) ............................................................................................................ 149
Grondsubstantie (tussenstof) ...................................................................................................... 149
Afbraak ECM ................................................................................................................................ 155
Basale lamina................................................................................................................................... 156
Metabolisme ....................................................................................................................................... 158
Fermentatie ..................................................................................................................................... 159
Warburg effect ............................................................................................................................ 160
3
, Mitochondriën ............................................................................................................................. 161
Metabolische drugs ..................................................................................................................... 166
Elektronendragers ....................................................................................................................... 167
Acetyl CoA ....................................................................................................................................... 172
Synthese acetyl CoA .................................................................................................................... 173
Epigenetica .................................................................................................................................. 173
Oorzaak of gevolg ............................................................................................................................ 176
Opname van glucose ................................................................................................................... 177
Vetzuursynthese .......................................................................................................................... 178
Pyruvaat kinasen (PKM1/M2)...................................................................................................... 180
Omzetting van pyruvaat .............................................................................................................. 181
Omgeving......................................................................................................................................... 181
Kanker.................................................................................................................................................. 182
Nomenclatuur.................................................................................................................................. 183
Epitheliale tumoren ..................................................................................................................... 183
Mesenchymale tumoren ............................................................................................................. 184
Uitzonderingen ............................................................................................................................ 185
Incidentie en mortaliteit.................................................................................................................. 185
Tumorgroei ...................................................................................................................................... 187
Genetische afwijkingen ................................................................................................................... 188
Omgeving en leefstijlfactoren ..................................................................................................... 188
Tumorigenese .................................................................................................................................. 189
Metastase ........................................................................................................................................ 192
Hallmarks ......................................................................................................................................... 193
Cancer-critical genes ................................................................................................................... 194
Proto-oncogen ............................................................................................................................. 197
Tumor-suppressor gen ................................................................................................................ 198
Epigenetische inactivatie ............................................................................................................. 199
Herstel DNA schade ..................................................................................................................... 200
Chromosomale afwijkingen ............................................................................................................. 204
Behandeling van kanker .................................................................................................................. 209
Kinasen als drugtargets ............................................................................................................... 210
Organoïden ...................................................................................................................................... 216
Tumor organoïden ....................................................................................................................... 216
Immunotherapie.............................................................................................................................. 222
Voor- en nadelen ......................................................................................................................... 225
4
, Vesiculair transport
Vesiculair transport is noodzakelijk voor het uitwisselen van componenten tussen de verschillende
organellen zonder dat de identiteit van de compartimenten verloren gaat. Hierbij snoeren er vesikels
van de membranen af, die een bepaalde inhoud (cargo) bevatten. Vervolgens fuseren deze vesikels
met het membraan van een ander compartiment, waardoor de inhoud (cargo) aan de cel afgegeven
wordt.
Figuur 1 Schematische weergave van vesiculair transport.
Er zijn verschillende manieren waarop vesiculair transport plaats kan vinden, dit is hieronder
weergegeven in een 'roadmap'. De verschillende transportroutes zijn als volgt:
• Endocytose → Hierbij worden stoffen uit de externe omgeving opgenomen via endosomen.
• Exocytose → Hierbij vindt secretie van stoffen plaats.
• Retrieval → Hierbij worden de lipiden die gebruikt worden voor het vormen van vesikels
terug naar het ER gebracht (gerecycled).
Figuur 2 Schematische weergave van de 'roadmap' van vesiculair transport.
5
