Week 8 - L4

Introduction to Cell Death

  • Focus of this section: Understanding apoptosis and its relevance in cancer.

  • Importance of the topic: Significant for the upcoming cancer unit.

  • Personal reflection: The speaker's passion stems from conducting PhD research in this area.

Overview of Cell Death

  • Types of Cell Death:   - Apoptosis: Programmed cell death, which is a normal physiological process.   - Necrosis: An undesirable form of cell death associated with damage and inflammation.

Apoptosis

  • Definition: A vital process that helps remove diseased, damaged, or unneeded cells from the body.

  • Importance during:   - Development: Removes cells that are no longer required.   - Disease management: Helps eliminate precancerous and damaged cells.

Mechanism of Apoptosis

  • Process overview:   - Cells undergo fragmentation, membrane blebbing, and are engulfed by phagocytes.   - Electron micrograph images help illustrate these phenomena.

  • Coordination Mechanism:   - Apoptosis is tightly regulated by molecular mechanisms within the cell.

Pathways of Apoptosis

  • Broad pathways:   - Extrinsic Pathway: Triggered by external signals (death signals).   - Intrinsic Pathway: Triggered by internal cell stimuli (e.g., DNA damage).

Key Molecular Events

  • Common events in apoptosis:   - Mitochondrial Outer Membrane Permeabilization (MOMP):     - Release of cytochrome c, which further promotes apoptosis.   - Formation of the apoptosome, leading to downstream activation of effector proteins.

Protein Families in Apoptosis

Caspase Family

  • Types of Caspases:   - Initiator Caspases: Start the apoptosis process (e.g., caspases 8 and 9).   - Effector (Executioner) Caspases: Carry out the cell dismantling.     - Examples include caspases 3, 6, and 7.

  • Mechanism:   - Caspases remain inactive until activated by apoptotic signals.   - Upon activation:     - Initiator caspases dimerize and cleave their pro domain, forming active dimers.     - Effector caspases are initially in a dimerized form and are activated by cleavage.

Role of Effector Caspases

  • Example: Caspase 3 is pivotal in DNA fragmentation and is activated by CAD (caspase-activated DNase).

  • Mechanisms of action:   - Active CAD cleaves chromatin and DNA, leading to cell fragmentation.

Visualization of Apoptosis

  • DNA fragmentation observed through:   - DNA gels showing intact genomic DNA initially, followed by fragmentation over time post-apoptosis induction.   - Fluorescent microscopy images depicting DNA condensation and cell blebbing indicative of apoptosis.

Apoptotic Pathway Specificity

  • Unique and common caspases:   - Caspases 8 and 10: Unique to the extrinsic pathway.   - Caspase 9: Common to both intrinsic and extrinsic pathways.

  • Activation is a self-perpetuating process: Once triggered, it leads to irreversible apoptosis.

Summary and Next Steps

  • Conclusion: Understanding the caspase family is fundamental to grasping the overall apoptosis process.

  • Next focus: Investigation of the Bcl-2 family and additional key events in apoptosis related to cancer.