Updated: 9/19/2019

Apoptosis

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Overview
  • Programmed cell death 
    • requirements
      • ATP
      • functioning caspase enzymes for cellular degradation 
        • break down cytoskeleton
        • degrade DNA
        • endonucleases cut at internucleosomal regions, resulting in segments that are multiples of 180 base pairs 
  • Two pathways
    • intrinsic
      • occurs in response to cell injury, loss of stimulatory growth factors, or DNA damage
      • involved in embryogenesis
      • mediated by changes in levels of anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) factors
        • leads to ↑ mitochondrial permeability and release of cytochrome c 
          • release of cytochrome c activates caspase-9
        • Bcl-2 binds to cytochrome c preventing apoptosis and inhibits Apaf-1 (promotes activation of caspases)
          • overexpression of Bcl-2 leads to a ↓ in apoptosis leading to an ↑ of tumorigenesis.
          • p53 degrades Bcl-2 to promote apoptosis when DNA damage is severe
    • extrinsic
      • occurs in response to several external "death" signals
        • FAS ligand binding the FAS death receptor (CD95) 
          • CD95 mediates a cascade of caspase activation via FADD, a death domain-containing adapter protein
        • Also mediated by TNF which acts in a similar fashion to FAS
        • killer CD8 T-cells kill virally infected cells
          • release perforin and granzyme B which damage the cell membrane and activate caspases
  • Mechanism
    • caspase cascade
      • regulation
        • pro-apoptotic factors
          • Bax 
            • activated by p53
              • absent in Li-Fraumeni syndrome
                • presents with high frequency of solid tumors
            • antagonizes Bcl-2
            • promotes release of mitochondrial cytochrome c into the cytosol
        • anti-apoptotic factors
          • Bcl-2 
            • prevents cytochrome c from being released and thus inhibits activation of caspase-9
      • caspases - inactive enzymes such as proteases and endonucleases
        • activated by intrinsic and extrinsic pathways
        • endonuclease activity leads to pyknosis (nuclear condensation)
        • protease activity leads to cytoskeleton breakdown
      • membrane begins to bleb containing cellular fragments
        • apoptotic bodies break off and are phagocytosed by macrophages
  • Key principles
    • distinct histological changes
      • cell shrinkage
      • pyknosis
      • eosinophilic cytoplasm
      • membrane blebbing
      • nuclear fragmentation (karyorrhexis)
      • nuclear fading
      • formation of apoptotic bodies
    • lack of inflammation
    • typically involves single or specific groups of cells leaving tissue architecture intact
  • Examples
    • menstrual shedding of endometrium
      • apoptosis induced in the endometrium when estrogen and progesterone levels decrease
    • destruction of specific cells during embyrogenesis
      • loss of Mullerian structures in males due to Mullerian inhibititory factor
    • virally infected cells
      • apoptosis induced by cytotoxic T-cells
    • embryogenesis
      • apoptosis induced in skin between fingers
 

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