Apoptosis Overview
Pathway Description:
Apoptosis is a regulated cellular suicide mechanism characterized by nuclear condensation, cell shrinkage, membrane blebbing and DNA fragmentation. Caspases, a family of cysteine proteases, are the central regulators of apoptosis. Initiator caspases (including caspase-2, -8, -9, -10, -11 and -12) are closely coupled to pro-apoptotic signals. Once activated, these caspases cleave and activate downstream effector caspases (including caspase-3, -6 and -7), which in turn execute apoptosis by cleaving cellular proteins following specific Asp residues. Activation of Fas and TNFR by FasL and TNF, respectively, leads to the activation of caspase-8 and -10. DNA damage induces the expression of PIDD which binds to RAIDD and caspase-2 and leads to the activation of caspase-2. Cytochrome c released from damaged mitochondria is coupled to the activation of caspase-9. XIAP inhibits caspase-3, -7 and -9. Mitochondria release multiple pro-apoptotic molecules, such as Smac/Diablo, AIF, HtrA2 and endoG, in addition to cytochrome c. Smac/Diablo binds to XIAP which prevents it from inhibiting caspases. Caspase-11 is induced and activated by pathological proinflammatory and pro-apoptotic stimuli and leads to the activation of caspase-1 to promote inflammatory response and apoptosis by directly processing caspase-3. Caspase-12 and caspase-7 are activated under ER stress conditions. Anti-apoptotic ligands including growth factors and cytokines activate Akt and p90RSK. Akt inhibits Bad by direct phosphorylation and prevents the expression of Bim by phosphorylating and inhibiting the Forkhead family of transcriptional factors (FKHR). FKHR promotes apoptosis by upregulating proapoptotic molecules such as FasL and Bim.
Selected Reviews:
- Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116(2), 205–19.
- Degterev A, Boyce M, Yuan J (2003) A decade of caspases. Oncogene 22(53), 8543–67.
- Yan N, Shi Y (2005) Mechanisms of apoptosis through structural biology. Annu. Rev. Cell Dev. Biol. 21, 35–56.
CST would like to thank Prof. Junying Yuan, Harvard Medical School, Boston, Massachusetts, for reviewing this diagram.
created January 2002 • revised January 2007
