Lecture 21

• Apoptosis


  Programmed cell death
• Apoptosis


  • Cells undergo apoptosis when they become damaged or infected and threaten the health of the organism
  • Apoptotic cells undergo massive changes
• Necrosis


  Cells die in response to an acute injury
• Necrosis


  • Necrotic cells swell and burst
  • Spills cellular content out and induces inflammatory response
• Caspases


  Intracellular proteases that degrade protein
• Procaspases


  Inactive caspases
• Initiator caspases


  • Activated by apoptotic signals (like DNA damage)
  • They activate executioner caspases
• Executioner caspases


  • Carry out apoptosis
  • They degrade nuclear lamins, cytoskeleton and cell adhesion proteins
• Intrinsic pathway of apoptosis

  1. Activated by signals created by mitochondria inside cell

  2. Activated in response to DNA damage

  3. Regulated by pro-apoptotic (death) and anti-apoptotic (survival) signals
• Intrinsic pathway of apoptosis

  • Mitochondria releases cytochrome c in response to pro-apoptotic signals
• Cytochrome c


  Activates initiator caspases (caspase 9) to induce apoptosis
• Bak


  • Pro-apoptotic Bcl2 protein
  • Opens channels to promote release of cytochrome c
• BclxL


  • Anti-apoptotic Bcl2 protein
  • Keeps channels closed
• Survival factors


  • Inhibit apoptosis
  • Activate a transcription factor that promotes expression of anti apoptotic Bcl2 proteins
• p53


  • Transcription factor that regulates the expression of over 200 genes
  • Binds to DNA as a tetramer as a response to cellular stress
  • Known as the guardian of the genome bc it can promote apoptosis
• Regulation of p53 gene expression

  1. P53 gene is constantly expressed

  2. P53 protein binds to DNA as a tetramer → targets genes are expressed

  3. Mdm2 adds ubiquitin to the p53 protein

  4. P53 protein is degraded by the proteosome
• DNA damage


  Generates stable active p53 bc it promotes phosphorylation of p53
• Unphosphorylated p53


  Inactive, binds to mdm2 and is degraded
• Phosphorylated p53


  Active, binds to DNA to activate gene expression
• ATM kinase


  DNA damage activates ATM kinase which phosphorylate p53
• DNA damage


  Activates ATM kinase
• p53


  Will induce cell cycle arrest or apoptosis depending on the amount of DNA damage
• p53 influence on apoptosis

  1. Low amount of DNA damage = increase of cdk inhibitors to stop cell cycle; use DNA repair pathways to fix damage

  2. High amount of DNA damage = too severe for DNA repair and increases expression of pro apoptotic genes to activate apoptosis