1. 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

2. Morphological Changes Distinct from necrosis: injured cell bursts, inflammatory response Apoptosis: orderly intracellular changes, dying cell phagocytosed

3. Caspases Protease with cysteine at active sites Cleave substrates at specific aspartic acids Synthesized as procaspases and activated by other caspases

4. Caspase Cascade Amplifying cascade involving initiator and executioner caspases Executioner caspases cleave substrates responsible for cell death

5. Induction Of Caspase Cascade Adaptor proteins aggregate initiator procaspases Mutual cleavage of weakly active procaspases Different adaptors activated by intracellular or extracellular stimuli

6. Ligand induces aggregation of death receptors on cell surface Death receptors recruit adaptor proteins that bind and aggregate initiator procaspases Extrinsic Pathway

7. Intrinsic Pathway Mitochondria induced to release cytochrome c Cytochrome c causes aggregation of Apaf-1 adaptor proteins that aggregate initiator procaspases

8. 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

9. BH123 Pro-Apoptotic Proteins Stimulate release of cytochrome c Required for intrinsic pathway

10. Anti-Apoptotic Bcl2 Family Bind to and inhibit pro-apoptotic Required for cell survival Inhibited during intrinsic pathway

11. BH3-Only Pro-Apoptotic Proteins Bind to and inhibit anti-apoptotic Activated by apoptotic stimuli (deprivation of survival factors, p53 response to DNA damage)

12. Survival Factors Cells deprived of survival factors activate intracellular death program Competition for survival factors can regulate cell number

13. Mechanism Of Survival Factors Signaling through Bcl2 family Transcriptional activation of anti-apoptotic Bcl2 proteins Akt kinase inactivates BH3- only pro-apoptotic protein, allowing Bcl2 to suppress apoptosis