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Apoptosis and Senescence

Mutant celegans mutants reveal apoptotic pathway no

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mutant
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C.elegans mutants reveal apoptotic pathway No cell death ced-3 ced-4 egl-1 Excessive cell death ced-9 Double mutant analysis to determine order of pathway: (note: for epistasis analyses the two mutants must have distinct phenotypes) ced-3/ced-9---> no cell death ced-4/ced-9---> no cell death egl-1/ced-9---> excessive cell death 13
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CED-3 and CED-4 are killer proteins CED-9 suppresses apoptosis The order of the pathway is C. elegans genetics revealed … 14 Video of apoptosome activation and caspase cascade http://www.youtube.com/watch?v=9KTDz-ZisZ0
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Apoptotic pathway is conserved in vertebrates EGL-1 = Bid,Bim (BH3) only binds to CED-9/Bcl-2 changes CED-9/Bcl-2 affinity for CED-4 transcriptionally induced in response to death signal CED-9 = Bcl-2 family member binds to and inhibits CED-4/Apaf1 CED-4 = Apaf1 acts as scaffold and activator protein for caspases multimeric form called apoptosome CED-3 = Caspase-9 (initiator) protease that activates caspases pre-protein form that is activated by Apaf-1 autocleaves 15
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Caspase Activation EGL-1 binds CED-9 Releases CED-9 inhibition on CED-4 CED-4 oligomerizes CED-3 binds to CED-4 oligomer Bound CED-3 is activated and autocleaves Activated and cleaved CED-3 initiates a caspase cascade Cell dies 16
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Apoptosis is centralized in the mitochondria Outer membrane proteins Bcl-2 BH3 only proteins Bax (forms a pore in membrane) Intermembrane space protein Cytochrome c released from IMS through Bax channel Cytosolic Bad (binds and inhibits Bcl-2) Apaf-1 Caspases 17
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Apaf1 activation in response to cytochrome c 18
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Bad inhibits Bcl-2 Unphosphorylated Bad binds to Bcl-2 Binding prevents Bcl-2 association with Bax Bax homodimer forms pore where cytochrome c is released Cytochrome c binds and activates Apaf1 Apoptosome activates caspase-9 Caspase-9 cleaves and activates effector caspases like caspase-3 Effector caspases cleave specific cellular proteins and lead to the cell’s ultimate demise 19
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PI3K signaling inhibits apoptosis Trophic Factor binds and activates PI3K signaling pathway
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