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

• Ligand induces aggregation of death receptors on cell surface• Death receptors recruit adaptor proteins that bind and

aggregate initiator procaspases

Extrinsic Pathway

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 BH3-

only pro-apoptotic protein, allowing Bcl2 to suppress apoptosis