What pathways lead to cellular apoptosis?
Multiple triggers can lead to a cell undergoing apoptosis by one of two major pathways:
Death receptors (Fas [CD95], TNF receptor 1 [TNFR1], DR4/5): all of these receptors have a homologous intracellular region “death domain.” These death domains bind to adaptor protein (Fas and DR4/5 binds to FADD, TNFR1 to TRADD). These adaptor proteins can activate the cysteine protease, procaspase 8. This can be inhibited by FLIP. The activated caspase 8 activates the executioner caspases (3, 6, and 7), which in turn activate an endonuclease called caspase-activated DNAse as well as others. These endonucleases cleave DNA causing fragmentation and cell death. Caspases also activate proteases that act on actin microfilaments leading to blebbing of the membrane.
• Mitochondria: cellular stress causes Bax, Bak, and/or Bid to bind to mitochondria. This displaces Bcl-2 and Bcl-x, which are normally on the outer mitochondrial membrane and inhibit apoptosis. When this happens, cytochrome c is released from the mitochondria. Cytochrome c activates the adaptor protein, Apaf-1, which is in the cytosol. Apaf-1 activates procaspase-9, which activates caspases 3 and 7 causing apoptosis (as mentioned earlier). Akt inhibits this pathway. Many tumors have chronically activated Akt, so the tumor cell does not undergo apoptosis.
• Others: (1) cytotoxic cells (T and NK cells) inject granzyme B, which activates caspases 3 and 7. (2) DNA damage is detected by p53, resulting in activation of apoptosis.