Regulation of Apoptosis

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 Endo G, in addition to cytochrome c. Smac/Diablo binds to XIAP, preventing it from inhibiting caspases. Caspase-11 is induced and activated by pathological pro-inflammatory and pro-apoptotic stimuli and leads to the activation of caspase-1, thereby promoting 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 transcription factors (FoxO). FoxO promotes apoptosis by upregulating pro-apoptotic molecules such as FasL and Bim.

Selected Reviews:

• Degterev A, Yuan J (2008) Expansion and evolution of cell death programmes. Nat. Rev. Mol. Cell Biol. 9(5), 378–90.
• Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell 147(4), 742–58.
• Indran IR, Tufo G, Pervaiz S, Brenner C (2011) Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim. Biophys. Acta 1807(6), 735–45.
• Kaufmann T, Strasser A, Jost PJ (2012) Fas death receptor signalling: roles of Bid and XIAP. Cell Death Differ. 19(1), 42–50.
• Kurokawa M, Kornbluth S (2009) Caspases and kinases in a death grip. Cell 138(5), 838–54.
• Pradelli LA, Bénéteau M, Ricci JE (2010) Mitochondrial control of caspase-dependent and -independent cell death. Cell. Mol. Life Sci. 67(10), 1589–97.
• Van Herreweghe F, Festjens N, Declercq W, Vandenabeele P (2010) Tumor necrosis factor-mediated cell death: to break or to burst, that's the question. Cell. Mol. Life Sci. 67(10), 1567–79.

We would like to thank Prof. Junying Yuan, Harvard Medical School, Boston, MA, for reviewing this diagram.

created September 2008

revised November 2012