FAS Receptor Activation and Apoptosis Pathways

Apoptosis

• A process of programmed cell death that occurs via an ordered sequence of events during growth and development of an organism.
• Morphological features:
  • Cell shrinkage
  • Karyolysis, pyknosis, and karyorrhexis
  • Disrupted cell membrane
  • Cytoplasm retained in apoptotic bodies
  • Inflammation usually present

Apoptosis in Cancer

• Apoptosis prevents cancer by culling cells at risk of transformation.
• Apoptosis suppresses tumourigenesis in various ways, including:
  • Induction of anoikis, a form of apoptosis that occurs when cells detach from the extracellular matrix (ECM).
• For cancer to initiate and progress, apoptosis must be inhibited at multiple stages, typically through the intrinsic pathway.

Anoikis

• A form of apoptosis that occurs when cells detach from the ECM.
• Activation of anoikis pathways:
  • Lack of ECM contact or engagement with inappropriate ECM leads to decrease of anti-apoptotic pathways.
  • Activation of death receptors and mitochondria.
  • Intrinsic pathway induced by up-regulation of pro-apoptotic molecules.
  • Extrinsic pathway activated through increased expression of Fas receptors.

p53

• A key player in cell cycle regulation, development, differentiation, gene amplification, DNA recombination, chromosomal segregation, and cellular senescence.
• p53 is called the "guardian of the genome".
• Defects in p53 have been linked to more than 50% of human cancers.
• p53 induces apoptosis by upregulating expression of Noxa and Puma BH3-only proteins in response to substantial levels of DNA breaks and other chromosomal abnormalities.

TP53 Mutations in Cancer

• Most mutations in TP53 detected in cancer cells are point mutations in the DNA-binding domain.
• 90% of mutant p53 proteins derive from missense mutations that allow the production of a full-length protein with a dramatically increased half-life.

Inhibitor of Apoptosis Proteins (IAPs)

• A group of structurally and functionally similar proteins that regulate apoptosis, cytokinesis, and signal transduction.
• X-chromosome linked, XIAP is the most potent inhibitor of apoptosis and the best-characterized IAP.