Lecture Notes: Apoptosis Initiation Pathways

Introduction

• Discussion on apoptosis, focusing on two initiation pathways:
  • Intrinsic Pathway: Initiated from inside the cell.
  • Extrinsic Pathway: Initiated from outside the cell via receptors.

Intrinsic Pathway

• Definition: A pathway where the cell destroys itself from the inside.
• Key Molecule: p53 can trigger this pathway.
• Mechanism:
  • p53 stimulates either Bax or Bak to release cytochrome C from the mitochondria.
  • Cytochrome C, normally part of the electron transport chain, acts as a signal for cell suicide when released into the cytoplasm.
• Process:
  • Cytochrome C binds to adapter proteins, forming a complex (often depicted as a seven-armed star).
  • This complex loads and activates procaspase-9.
  • Activation of caspase-9 leads to the formation of the apoptosome (complex of adapter proteins and caspase-9).
  • Caspase-9 cleaves and activates executioner caspases (caspase-3), leading to cell death.

Extrinsic Pathway

• Definition: Initiated by external signals via cell surface receptors.
• Key Components:
  • Death receptors on the cell surface respond to external signals.
  • Notable receptors include Fas (Fatty Acid Synthase) and Tumor Necrosis Factor Receptors (TNFR).
• Mechanism:
  • External signals bind to death receptors, activating their intracellular domains.
  • These receptors contain initiator caspases (caspase-8 and caspase-10).
  • Upon activation, initiator caspases are cleaved and activate a cascade involving executioner caspases.
• Outcome: The executioner caspases dismantle the cell, including the cytoskeleton, resulting in cell death.

Observation & Identification

• To determine the pathway of apoptosis being utilized:
  • Check for the cleavage of initiator caspases.
  • If initiator caspases are cleaved, likely the extrinsic pathway is active.

Conclusion

• Apoptosis can proceed via intrinsic or extrinsic pathways.
• Each pathway involves specific proteins and mechanisms to induce cell death.
• Understanding which pathway is active can provide insights into the cellular context and triggers involved.