Key Concepts of Section 21.5

• All cells require trophic factors to survive. In the absence of these factors, cells commit suicide.

• Genetic studies in C. elegans have defined an evolutionarily conserved apoptotic pathway with three major components: membrane-bound regulatory proteins, cytosolic regulatory proteins, and apoptotic proteases (called caspases in vertebrates) (see Figure 21-35).

• Once activated, apoptotic proteases called caspases cleave specific intracellular substrates, leading to the demise of a cell. Other proteins (e.g., CED-4, Apaf-1) that bind regulatory proteins and caspases are required for caspase activation (see Figures 21-35, 21-36, and 21-41).

• Survival of motor and sensory neurons during development is mediated by neurotrophins released from target tissues that bind to Trk receptor tyrosine kinases on the neuronal growth cones (see Figure 21-38), activating an anti-apoptotic response via the PI-3 kinase pathway (see Figure 21-40).

• The Bcl-2 family contains both pro-apoptotic and anti-apoptotic proteins; most are transmembrane proteins and engage in protein-protein interactions.

• In mammals, apoptosis can be triggered by oligomerization of Bax or Bak proteins in the outer mitochondrial membrane, leading to efflux of cytochrome c and SMAC/DIABLO proteins into the cytosol; these proteins then promote caspase activation and cell death.

• Bcl-2 proteins can restrain the oligomerization of Bax and Bak, inhibiting cell death.

• Pro-apoptotic BH3-only proteins (e.g., Puma, Bad) are activated by environmental stress and stimulate the oligomerization of Bax and Bak, allowing cytochrome c to escape into the cytosol, bind to Apaf-1, and thus activate caspases.

• Direct interactions between pro-apoptotic and anti-apoptotic proteins lead to cell death in the absence of trophic factors. Binding of extracellular trophic factors can trigger changes in these interactions, resulting in cell survival (see Figure 21-40).

• Binding of extracellular death signals, such as tumor necrosis factor and Fas ligand, to their receptors oligomerizes an associated protein (FADD), which in turn triggers the caspase cascade, leading to cell murder by apoptosis.

• In the absence of caspase-8, tumor necrosis factor induces necroptosis. Intracellular proteins released into the surroundings as a result can cause inflammation and tissue damage.