Apoptosis Study Notes

Apoptosis

BIOL 2070 Lecture 22
Suggested Readings

  • Chapter 18

Overview

Important Dates

Introduction to Cell Cycle

  • Entry into the cell cycle: An all or nothing response.

    • Mitogens: Extracellular signals (often growth factors) that initiate cell cycle entry.

    • Exit from Cell Cycle: The only exit is through cell death.

Apoptosis Defined

What is Apoptosis?

  • Apoptosis (programmed cell death): An all or nothing response initiated by pro-apoptotic intracellular signaling pathways.

  • Necrosis: Accidental cell death characterized by swelling, membrane rupture, and inflammation.

Differences Between Apoptosis and Necrosis

  • Necrosis:

    • Cell swells

    • Membrane ruptures

    • Cytosol spills out leading to inflammation.

  • Apoptosis:

    • Cell membrane remains intact

    • Cytosol contained

    • No inflammation response triggered.

Hallmarks of Apoptosis

Features of Apoptotic Cells

  1. Cell Membrane Changes: Collapse into blebs.

  2. DNA Breakdown: DNA is fragmented.

  3. Surface Changes: The cell surface alters to attract phagocytes (e.g., macrophages).

  4. Phagocytosis: Apoptotic cells are engulfed by macrophages before releasing contents, preventing inflammation.

Process Overview

  • Apoptotic Process:

    1. Chromosomal DNA fragmentation.

    2. Nucleus breaks into pieces.

    3. The cell shrinks and forms apoptotic bodies (blebbing).

    4. Apoptotic bodies are rapidly phagocytized and removed.

  • Eat Me Signal: Apoptotic cells express phosphatidylserine on their surface, signaling macrophages to phagocytize.

    • Normally, phosphatidylserine is on the cytosolic side but during apoptosis is translocated to the extracellular side.

Purpose of Apoptosis

Functions of Apoptosis

  1. Cell Regulation: Balances cell proliferation and death.

  2. Removal of Unneeded Cells: Crucial during development and organ repair.

  3. Elimination of Misbehaving Cells: Removes damaged or transformed cells without invoking an immune response.

Developmental Role

  • Sculpting Analogy: "How do you sculpt a David? You chip away everything that isn’t David" (attributed to Michelangelo).

    • Apoptosis sculpts organs, such as during digit formation in embryonic mice.

Mechanism of Apoptosis

Cellular Steps in Apoptosis

  • Chromosomal DNA fragmentation.

  • Nucleus fragmentation.

  • Cellular shrinkage and blebbing.

  • Formation of membrane-enclosed apoptotic bodies for phagocytosis.

Regulation of Apoptosis

Role of Caspases

  • Caspases: Serine proteases that execute apoptosis.

    • Break down over 100 different target proteins.

    • Activation leads to apoptotic changes in the cell.

Targets of Caspases

  1. Inhibitor of DNase → DNA fragmentation.

  2. Nuclear Lamins → Nucleus fragmentation.

  3. Cytosolic Cytoskeletal Proteins → Disruption of cytoskeleton leading to membrane blebbing.

  4. Golgi Membrane Proteins → Golgi fragmentation.

  5. Scramblase → Translocation of phosphatidylserine to the cell surface.

Activation of Caspases

  • Inactive caspases are expressed in all cells, making them primed for apoptosis.

Bcl-2 Family Proteins

Overview of Regulation

  • Bcl-2 Family: Regulate apoptosis and comprise anti-apoptotic and pro-apoptotic proteins, named after B cell lymphoma (Bcl-2).

    • Each member has a conserved domain known as BH3.

Types of Bcl2 Proteins

  1. Antiapoptotic Regulatory Proteins (ARP): Inhibit caspase activity.

  2. Proapoptotic Regulatory Proteins (PRP): Indirectly induce caspase activity.

  3. Proapoptotic Effector Proteins (PEP): Directly activate caspase activity.

Examples

  • Bcl2: The founding member of the Bcl-2 family, discovered in 1982. It is the first oncogene linked to cancer by inhibiting apoptosis.

Dance of Bcl-2 Family

Interactions Among Bcl-2 Proteins

  • The interactions among these three groups determine cell fate, described as a "dance" that regulates apoptosis.

    • The fate of a cell relies on the net interactions of Bcl-2 proteins.

Granule of Clinical Research

Importance of Bcl2 Proteins in Medicine

  • Clinical trials are being conducted to test Bcl-2 inhibitors such as venetoclax for treating various cancers, illustrating the relevance of apoptosis in clinical settings.

Induction of Apoptosis

Signals and Pathways
DNA Damage

  1. Role of p53:

    • Activates in response to DNA damage, increasing activity of P21 to block Cyclin/CDK complexes.

    • Triggers apoptosis if damage is too severe.

Extracellular Pro-survival Factors

  • Function: Inhibit apoptosis through signals received from other cells, keeping cells alive.

    • Major pathway initiated by PI-3 Kinase to promote cell survival.

Extrinsic and Intrinsic Pathways

  • Intrinsic Apoptosis: Triggered by DNA damage or loss of survival signals.

  • Extrinsic Apoptosis: Triggered by tumor necrosis factor (TNF) family members, activating caspase-8 directly.

Importance of Extrinsic Apoptosis

  • Plays a critical role in normal development by sculpting tissues during embryogenesis.

Conclusion

Historical Context

  • Cell Theory: Proposed by Theodor Schwann and Matthias Jakob Schleiden in 1837, asserting that all living things consist of one or more cells, forming the foundational principle of modern biology.

  • Cells have dual lives: individual development and as part of a collective organism.