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
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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