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17 Cards in this Set
- Front
- Back
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What are the overall mechanisms (pathways) initiating apoptosis? |
- intrinsic pathway (mitochondrial) - extrinsic pathway (receptor mediated) - granzyme B mediated |
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What initiates the intrinsic pathway? |
- Growth factor OR withdrawal of survival factor - DNA damage (radiation or toxins) via p53 - Protein misfolding (ER stress) |
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What is the mitochondrial pathway? |
- BCL-2 (B-cell lymphoma) is key family - when pro-apoptotic members bind - pores open and cytochrome C is released = DEATH - when anti-apoptotic members bind - pores close = LIFE |
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What are the 3 subfamilies of the BCL-2 family? |
- Anti-apoptotic/pro-survival members (4BH domains and a transmembrane domain) - Pro-apoptotic members (lack BH4 domain but contain TM domain - form pores in mit membrane allowing release of cyt c) - BH-3 only proteins - only contain BH3; activate pro-apoptotic members |
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What are some key BCL-2 family interactions? |
- BCL2 inhibits apoptosis by preventing release of cyt c from mitochondria - Bax family - reside in inactive monomer forms in outer membrane (Bak) or cytosol (Bax) = form channels or interact with components of membrane pore - allow cyt c release |
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Relationship between BCL-2 and Bax? |
- BCL-2 > Bax = apoptosis prevented - BCL-2 < Bax = apoptosis occurs |
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Describe the action of the intrinsic apoptosis pathway? |
- survival signals promote induction of BCL-2 which prevent Bax oligomer formation - Stress or damage induce sensors like BID and BAD - antagonise BCL-2 and allow Bax to form - if there is a leakage of cytochrome c caspase will be activated again |
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What are the different mammalian caspases (sim to Drosophila and C. elegans) and what are their features? |
- Initiator caspases - can auto-activate and exist as monomers in healthy cells - Effector caspases are present as pre-formed dimers - Caspases function as heterotetramers formed through dimerization of 2 dimers |
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How does the apoptosome form in mammals? |
- Cytochrome c binds to adaptor Apaf-1 - Apaf-1 undergoes conformationla change - enables Apaf-1s to bind together - form wheel-like apoptosome - activate pro-caspase-9 by conformational change OR by interaction between to apoptosomes - crossactivation |
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How does the apoptosome form in mammals (image) |
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What are some additional regulatory elements of apoptosis? |
- Pro-apoptotic - Smac/Diablo released alongised cyt c - inactivate inhibitors of apoptosis -Anti apoptotic - Survivin/XIAP - inhibit apoptosis (bind caspases/target them for degradation/prevent their accidental activation) |
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How do survival factors allow anti-apoptotic proteins like BCL-2 to exert their effects? |
- act via their receptors, which are receptor-tyrosine kinases - need to suppress natural instinct of the cell to commit suicide - e.g. of survival factors - growth factors - EGF, IGF etc. |
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Summary of main points so far: |
1) intrinsic pathway - induced by cell damage or loss of survival factors; involves release of cyt c to initiate apoptotic cascade of events 2) regulators of cascade - BCL-2, Smac/Diablo, IAPs and HSPs 3) BCL-2 contain anti and pro apoptotic members which oppose each other - change of ratio = apoptosis |
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Summary of main points pt2: |
4) survival signals suppress apoptosis; loss=apoptosis via intr. route; reg by growth factor induced signalling 5) Signalling sequence involves the PI3-kinase/PDK1/PKB (Akt)/BAD cascade 6) once phosphorylated BAD is sequestered by cytosolic proteins and cannot exert pro apoptotic effects |
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Comparison of aspects of apoptosis in vertebrates and invertebrates (image) |
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Comparison between Mammals and Drosophila: |
- Mammals: Ras/Raf/MAP kinase pathway ->ERK -> RSK phosphorylates and deactivates BAD - Drosophila - MAP kinase inactivates HID (phosphorylation)l IAPs are unaffected and unable to inhibit caspases |
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Relevance of PKB signalling in C. elegans and Mammals? |
- C. elegans - environmental cures - B=PBK signalling = reduced animal life span - Mammals - survival factors - PBK = suppression of apoptosis |
