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Download Purposes Of Apoptosis
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Purposes Of Apoptosis Eliminate cells not needed by organism • During development: sculpting, remove excess neurons • Adult – Maintain tissue size – Eliminate autoreactive immune cells, DNA damaged cells Morphological Changes • Distinct from necrosis: injured cell bursts, inflammatory response • Apoptosis: orderly intracellular changes, dying cell phagocytosed Caspases • Protease with cysteine at active sites • Cleave substrates at specific aspartic acids • Synthesized as procaspases and activated by other caspases Caspase Cascade • Amplifying cascade involving initiator and executioner caspases • Executioner caspases cleave substrates responsible for cell death Induction Of Caspase Cascade • Adaptor proteins aggregate initiator procaspases • Mutual cleavage of weakly active procaspases • Different adaptors activated by intracellular or extracellular stimuli Extrinsic Pathway • Ligand induces aggregation of death receptors on cell surface • Death receptors recruit adaptor proteins that bind and aggregate initiator procaspases Intrinsic Pathway • Mitochondria induced to release cytochrome c • Cytochrome c causes aggregation of Apaf-1 adaptor proteins that aggregate initiator procaspases Bcl2 Family • • • • Regulators of intrinsic pathway Pro- and anti-apoptotic types affect cytochrome c release Bind and inhibit each other’s activities Balance determines cells live or die BH123 Pro-Apoptotic Proteins • Stimulate release of cytochrome c • Required for intrinsic pathway Anti-Apoptotic Bcl2 Family • Bind to and inhibit pro-apoptotic • Required for cell survival • Inhibited during intrinsic pathway BH3-Only Pro-Apoptotic Proteins • Bind to and inhibit anti-apoptotic • Activated by apoptotic stimuli (deprivation of survival factors, p53 response to DNA damage) Survival Factors • Cells deprived of survival factors activate intracellular death program • Competition for survival factors can regulate cell number Mechanism Of Survival Factors • Signaling through Bcl2 family • Transcriptional activation of anti-apoptotic Bcl2 proteins • Akt kinase inactivates BH3only pro-apoptotic protein, allowing Bcl2 to suppress apoptosis
