Apoptosis

Types of Cell Death

  • Cell death by injury   * Mechanical damage   * Exposure to toxic chemicals
  • Cell death by suicide   * External signals   * Internal signals

Necrosis vs Apoptosis

  • Necrosis   * Cellular swelling   * Membranes are broken   * ATP is depleted   * Cell lyses, eliciting an inflammatory reaction    * DNA fragmentation is random, or smeared   * In vivo, whole areas of the tissue are affected
  • Apoptosis   * Cellular condensation   * Membranes remain intact   * Requires ATP   * Cell is phagocytosed, no tissue reaction    * Ladder-like DNA fragmentation   * In vivo, individual cells appear affected

Why Should A Cell Commit Apoptosis?

  • Apoptosis is needed for proper development   * Embryonic Morphogenesis     * The resorption of the tadpole tail     * The formation of the fingers and toes of the fetus    * The sloughing off of the inner lining of the uterus   * The formation of the proper connections between neurons in the brain   * Regulation of cell viability by hormones and growth factors (most cells die if they fail to receive survival signals from other cells)
  • Apoptosis is needed to destroy cells    * Cells infected with viruses   * Cells of the immune system   * Cells with DNA damage   * Cancer cells

What Makes a Cell Decide to Commit To Apoptosis?

  • Withdrawal of positive signals   * Examples :      * Growth factors for neurons     * Interleukin-2 (IL-2)
  • Receipt of negative signals   * Examples :      * Increased levels of oxidants within the cell      * Damage to DNA by oxidants      * Death activators :       * Tumor necrosis factor alpha (TNF-α)        * Lymphotoxin (TNF-β)        * Fas ligand (FasL)

Caspases

  • Caspases: specialized proteases that mediate apoptosis
  • Protease with cysteine at active sites
  • Cleave  substrates at specific aspartic acids
  • Synthesized as procaspases and activated by other caspases

Caspase Activation Amplification Cascade

  1. An inhibitor of a DNAse: leads to fragmentation of DNA
  2. Nuclear Lamina: leads to fragmentation of nucleus
  3. Other Cytoskeletal Associated Proteins: leads to disruption of cytoskeleton and cell fragmentation
  4. Additional Caspases

Main Pathways Regulating Caspase Activation During Apoptosis

  • Intrinsic Pathway- Mitochondrial Mediated Major Pathway in Mammalian Cells    * Outer Mitochondrial Membrane Permeabilization (MOMP)   * Release of Cytochrome C from Mitochondrial Intermembrane Space into Cytosol   * Apoptosome formation: Activation of Initiator Caspase    * Effector caspases activated
  • Extrinsic Pathway- Signaling through Death Receptors   * Ligand Bound Death Receptors   * Adaptor Protein Association   * Initiator Caspase Recruitment and Activation   * Used by Immune System

Critical Regulators of Cell Death

  • Bcl-2 Family– Regulate whether MOMP Occurs   * Anti-Apoptotic Factors: death inhibitors      * Function to inhibit MOMPs (Mitochondrial Outer Membrane Permeabilization) by pro apoptotic factors (aka death activators)   * Pro-Apoptotic Factors: death activators      * Bind and inhibit death inhibitors     * Directly cause MOMP to stimulate release of cytochrome C (BAX AND BAK)
  • IAP Family  (Inhibitor of Apoptosis)   * Bind Procaspases prevent activation   * Bind Caspases and inhibit Activity

Survival Factors

  • When cells are deprived of survival factors, they activate programmed cell death pathway
  • Survival factors usually act by binding to cell surface receptors    * Turn on signaling pathways that suppress cell death program   * Some increase production of Bcl2

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