Cancer and the Cell Cycle : An overview Ken Wu
Apr 01, 2015
Cancer and the Cell Cycle : An overview
Ken Wu
Disclaimer
• This tutorial is a simple and conceptual guide to the cancer module and the cell cycle
• If there are any conflicts between my slides and the lecturers, THE LECTURER IS ALWAYS RIGHT…
• …maybe not always but they set your exams so if in doubt, refer back to their teaching
The Cell Cycle
• Most adult cells, without growth stimulus, will go into the G0 phase of the cell cycle
• However, when a growth factor binds to its receptor on the cell membrane, a cascade starts and the cell prepares to enter G1
Growth stimulus
• Growth factors– Epidermal Growth Factor (EGF)– Platelet-Derived Growth Factor (PDGF)
• Binds to Receptors Protein Tyrosine Kinase (RPTK)
Preparing the cascade
• Grb2 (adaptor protein) binds to phosphorylated tyrosine– Recruits SoS (Ras activating protein)
• SoS exchanges GDP for GTP– Activates Ras
• Ras must be membrane bound to be active
The ERK Cascade
• RAS– Raf• MEK
– ERK
• Causes gene expression changes via proteins such as c-Myc
Cyclin dependent kinases (Cdk)
• Cyclically activated protein kinases• Activation depends on– Cyclin – Cdk interaction– Phosphorylation
• Cyclins– Expressed at different points in cell cycle– Transiently expressed and degraded
Cyclin – Cdk interation
• Cdk 4,6 + cyclin D (up regulated by c-Myc)– G0 – G1
– Also stimulates cyclin E synthesis• Cdk 2 + cyclin E– S phase entry
• Cdk 2 + cyclin A– Metaphase of mitosis entry
• Cdk 1 + mitotic cyclin (cyclin B)– Promotes mitosis
Cell cycle timing and direction
• Due to sequentially active Cdk, and synthesis of Cdk for the next phase of cell cycle
Cyclin – Cdk function
• Phosphorylate pRb protein• Phosphorylated pRb ‘releases’ E2F
transcription factor• E2F is now free to facilitate gene transcription
pRb
Cdk4/6
pRbpRbPP
P
Cdk2 Cdk2E2FE2FD E A
PP
Cdk1TF B
MitosispRb
Cdk inhibition
• INK4 family– Inhibit Cdk 4,6– G1 phase inhibitors
• CIP/KIP family– Inhibit all Cdks– S phase inhibitors
• Degradation allows cell cycle progression
The Big Picture
• G0 + EGF– RAS, Raf, MEK, ERK, c-Myc
• Cyclin – Cdk– D + 4,6 (G0 – G1)
– E + 2 (G1 – S)– A + 2 (Metaphase)– B + 1 (Anaphase)
Cancer – when it goes wrong
• Overexpressed EGFR• Mutant RAS– Does not dephosphorylate GTP– Constantly bound to GTP thus constantly active
• Overexpressed c-Myc, cyclin D• Inactive pRB
Apoptosis vs Necrosis - basics
• Necrosis– Unregulated– Trauma, cellular disruption– Inflammatory response
• Apoptosis– Regulated– Controlled disassembly– No inflammatory response
Apoptosis vs necrosis - process• Necrosis
– Plasma membrane becomes permeable– Cell swelling– Membrane rupture– Protease autodigestion– Localised inflammation
• Apoptosis– Activate death pathway– Cell shrinkage– Nuclear condensation– DNA fragmentation– Apoptotic bodies– Macrophages
Caspases
• Activation– Proteolysis– Cascade
• Initiator caspases– CARD or DED domain
• Effector caspases
Caspase function
• Initiator caspase– Activation via proteolytic cleavage– Caspase cascade
• Effector caspase– Cleave and inactive proteins– Activate enzymes in apoptosis
Receptor mediated caspase activation (extrinsic pathway)
• Fas receptor– Fas – Fas ligand interation– Has DD intracellular domain
• Recruits FADD – DD of FADD attaches to DD of Fas
• DED domain of FADD interacts with DED domain of caspase
• Recruits caspase 8– Caspase cascade– Cleaves Bid – mitochondrial pathway
• Process inhibited by FLIP
DED DDFADD
DED DEDFLIP
Mitochondrial death pathway (intrinsic pathway)
• Loss of mitochondrial membrane potential– Releases cytochrome c + other factors
• Forms apoptosome complex– Apaf 1
• Binds to cytochrome c• CARD domain binds to CARD of caspase 9
– Caspase cascade
• Needs ATP– Therefore energy levels decide apoptosis vs necrosis
Apoptosis modulators
• Bcl – 2 family– Anti – apoptotic• Bcl – 2• Bcl –xL
– Pro – apoptotic• Bid• Bad• Bax
Mechanism of apoptosis modulation
• Growth factor presence– PI3 – K pathway• PKB/Akt production
– Inactivates Bad, caspase 9
• Inhibited by PTEN
• Bax– Forms pore on mitochondrial matrix
Cancer – when it goes wrong
• Overexpressed Bcl – 2• Overexpressed PKB/Akt• Inactive PTEN
Any questions?
• Email me at [email protected]• Visit the ICSM Year 1+2 past paper bank
Facebook group/the note bank on the ICSMSU website
• Good luck with exams next term!