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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…
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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 – Cdkinteration • 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 E2F E A B D Cdk4/6 Cdk2 Cdk2 TF Cdk1 E2F Mitosis P P P pRb pRb pRb pRb P P
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
DED DD 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 FADD FLIP DED DED
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 ken.wu09@imperial.ac.uk • Visit the ICSM Year 1+2 past paper bank Facebookgroup/the note bank on the ICSMSU website • Good luck with exams next term!