Seminar 4 - Apoptosis

Apoptosis Overview

  • Definition: Apoptosis is the process of programmed cell death, crucial for maintaining tissue homeostasis.

  • Incidence: In adults, approximately 3 billion cells undergo apoptosis every minute to maintain balance with cell proliferation.

  • Functionality:

    • Restructuring tissues and organs during embryogenesis and development.

    • Elimination of immune T-cells and B-cells post-infection.

    • Regulation of wound healing.

Major Pathways of Apoptosis

  • P53 Induction: Critical for the initiation of apoptosis, particularly in response to DNA damage.

Differences Between Apoptosis and Necrosis

  • Apoptosis:

    • Cell shrinks without damaging nearby cells.

    • Non-inflammatory response; the remains are phagocytosed before content release.

    • Characterized by chromatin condensation and membrane blebbing.

  • Necrosis:

    • Cell swells and bursts, leading to the release of contents into the extracellular space, stimulating inflammation.

    • Often caused by infections or trauma.

Mechanism of Apoptosis

  • Signal Initiation: Initiated by various signals including:

    • Damaged DNA.

    • Incorrectly progressing cellular cycles.

    • Inadequate extracellular matrix contact and growth factors.

    • Presence of death signal proteins.

  • Involvement of Caspases:

    • Caspases are proteases activated during apoptosis, leading to cell death via several cellular changes.

Intrinsic and Extrinsic Pathways

  • Caspase Cascade Activation: The two primary pathways leading to caspase activation:

    • Extrinsic (Death Receptor Pathway): Initiated by death ligands binding to receptors on the target cell, activating pro-caspase 8, which triggers the apoptotic cascade through the formation of a DISC (death-inducing signaling complex).

    • Intrinsic (Mitochondrial Pathway): Regulated by the balance of pro-apoptotic and anti-apoptotic proteins (e.g., Bax, Bak, Bcl-2); cytochrome c release into the cytoplasm activates initiator caspase-9.

Key Proteins in Apoptosis Regulation

  • BH Domain Proteins: 24 known types in humans categorized as:

    • Anti-apoptotic (Bcl-2, Bcl-XL)

    • Pro-apoptotic (Bax, Bak)

    • Facilitator proteins (Bid, Bad).

Role of p53 in Apoptosis

  • Mechanisms:

    • P53 inhibits cell cycle progression in response to DNA damage by increasing p21 levels to halt the cell cycle.

    • If damage is too severe, p53 promotes apoptosis by upregulating pro-apoptotic genes (e.g., BAX, PUMA).

  • Degradation Regulation:

    • Maintenance of p53 levels via Mdm2, which targets it for degradation.

    • Stress conditions increase acetylation and phosphorylation leading to stabilization and activation of p53.

MAPK Pathways

  • Functions: Dual role in regulating cell death and survival through responses to cellular signals.

  • Specific MAPK Elements: Include JNK, which can promote apoptosis by reducing the activity of Bcl-2, facilitating pro-apoptotic signaling, while other MAPKs like Akt promote cell survival.

Conclusion

  • Apoptotic Pathway Regulation: Combination of signals determines whether a cell undergoes apoptosis or survives by integrating various external and internal stimuli, ensuring cells either proliferate or die as required by physiological needs.