AP Biology: Apoptosis – Programmed Cell Death (Signals, Caspases, Blebbing)

Apoptosis – Programmed Cell Death (Signals, Caspases, Blebbing)

Concept Summary

• Apoptosis: Programmed cell death triggered by internal or external signals, essential for development, immune response, and preventing cancer by removing damaged cells.
• Caspases: Cysteine-dependent aspartate-directed proteases that cleave specific proteins to execute apoptosis, existing as inactive zymogens (procaspases) until activated.
• Blebbing: Formation of membrane protrusions (blebs) during apoptosis due to cytoskeletal breakdown, facilitating phagocytic clearance of cell fragments.
• Intrinsic pathway: Mitochondria-mediated apoptosis initiated by intracellular stress (e.g., DNA damage), releasing cytochrome c to activate caspase-9.
• Extrinsic pathway: Death receptor-mediated apoptosis triggered by external ligands (e.g., FasL, TNF-?) binding to receptors (e.g., Fas, TNFR), activating caspase-8.

Core Questions

WHAT (definitional)

Q: What is apoptosis? A: A genetically regulated, energy-dependent process of controlled cell suicide to eliminate damaged or unnecessary cells without inflammation. Trap/Clarification: Apoptosis-necrosis (necrosis is unregulated, causes inflammation, and results from acute injury).

Q: What are caspases? A: Proteolytic enzymes that cleave target proteins at aspartate residues, driving the execution phase of apoptosis. Trap/Clarification: Caspases are not active in healthy cells; they are synthesized as inactive procaspases and require cleavage for activation.

WHY (causal/explanatory)

Q: Why is apoptosis important during development? A: It sculpts tissues (e.g., removing webbing between digits) and eliminates excess neurons to refine neural circuits. Trap/Clarification: Apoptosis is not random; it’s spatially/temporally precise (e.g., tadpole tail resorption during metamorphosis).

Q: Why does the intrinsic pathway rely on mitochondria? A: Mitochondria release cytochrome c in response to stress (e.g., DNA damage), which binds Apaf-1 to form the apoptosome and activate caspase-9. Trap/Clarification: Cytochrome c’s role in apoptosis is distinct from its function in the electron transport chain.

HOW (process/application)

Q: How is the extrinsic pathway activated? A: Death ligands (e.g., FasL) bind to death receptors (e.g., Fas), recruiting adaptor proteins (e.g., FADD) to form the DISC (Death-Inducing Signaling Complex), which activates caspase-8. Trap/Clarification: Caspase-8 directly activates executioner caspases (e.g., caspase-3) in the extrinsic pathway, unlike the intrinsic pathway’s apoptosome intermediate.

Q: How does blebbing occur? A: Caspases cleave cytoskeletal proteins (e.g., actin, lamin), causing membrane instability and bleb formation; blebs are then phagocytosed by macrophages. Trap/Clarification: Blebs are not passive swelling (like in necrosis); they’re actively formed and contain fragmented DNA/proteins.

CAN (conditions/possibilities)

Q: Can apoptosis be inhibited? A: Yes, by anti-apoptotic proteins (e.g., Bcl-2, IAPs) or survival signals (e.g., growth factors), which block cytochrome c release or caspase activation. Trap/Clarification: Overexpression of Bcl-2 (e.g., in cancer) prevents apoptosis, leading to tumor survival.

Q: Under what conditions does apoptosis fail? A: When pro-apoptotic signals (e.g., p53 activation) are suppressed (e.g., p53 mutations) or executioner caspases are inhibited (e.g., by viral proteins like CrmA). Trap/Clarification: Failed apoptosis does not always cause cancer (e.g., autoimmune diseases result from excessive lymphocyte survival).

Quick Facts & Traps

• Fact: Caspase cascade: Initiator caspases (e.g., -8, -9) activate executioner caspases (e.g., -3, -7) via proteolytic cleavage.
• Trap: "All caspases are pro-apoptotic"-Reality: Some caspases (e.g., caspase-1) function in inflammation, not apoptosis.
• Fact: Phagocyte "eat-me" signals: Apoptotic cells expose phosphatidylserine (normally inner leaflet) on the outer membrane to attract phagocytes.
• Trap: "Blebbing = necrosis"-Reality: Blebbing is apoptosis-specific; necrosis causes membrane rupture and spillage.
• Fact: p53’s role: DNA damage activates p53, which upregulates pro-apoptotic proteins (e.g., Bax, PUMA) to trigger the intrinsic pathway.
• Trap: "Apoptosis always requires ATP"-Reality: ATP is needed for caspase activation, but late-stage apoptosis can proceed without it (e.g., in energy-depleted cells).

Rapid-Fire True/False

• Statement: The extrinsic pathway requires mitochondrial involvement to activate caspases. Answer: FALSE Why the common mistake happens: Confusion with the intrinsic pathway’s reliance on cytochrome c release.

• Statement: Caspase-3 is an initiator caspase. Answer: FALSE Why the common mistake happens: Caspase-3 is an executioner caspase; initiators are -8 (extrinsic) and -9 (intrinsic).

• Statement: Apoptosis can be triggered by viral infection. Answer: TRUE Why the common mistake happens: Overlooking immune-mediated apoptosis (e.g., cytotoxic T cells using FasL to kill infected cells).