Apoptosis: Regulatory Genes and Disease

Abstract

Apoptosis is essential for normal development and proceeds by the extrinsic death receptor pathway, or the intrinsic Bcl‐2 blockable pathway. Both pathways activate a class of proteases termed caspases that cleave intracellular substrates resulting in cell death. Excessive apoptosis may excerbate neurological diseases and the damage caused by heart attacks and strokes. Apoptosis is used by metazoans as a defence against pathogens that have, therefore, evolved mechanisms to block the apoptotic machinery. The involvement of apoptosis in disease states has led to the rational design of compounds that target this pathway which are already successfully used in the clinic.

Key concepts

  • Apoptosis can occur by the extrinsic death receptor pathway or by the intrinsic Bcl‐2 blockable pathway.

  • Perforin–granzyme‐mediated toxicity is important for NK and T‐cell destruction of pathogen‐infected cells and tumour cell surveillance.

  • p53 is a transcription factor that prevents tumourigensis by initiating the intrinsic cell death pathway.

  • The Bcl‐2 protein family is made up of pro‐ and antiapoptotic proteins that form the core components of the intrinsic cell death pathway and are often dysregulated in cancer.

  • Death receptors regulate immune cell function and development by inducing apoptosis and also by stimulating pro‐survival cellular responses.

  • Rationally designed compounds specifically targeting the intrinsic or extrinsic cell death regulators are hoped to provide new and highly specific cancer therapies.

Keywords: apoptosis; death receptor; disease; cancer; immunity; genes

Figure 1.

Model for the intrinsic, or Bcl‐2 blockable, apoptosis pathway. Cell stresses, such as DNA damage induced by UV irradation, results in the transcriptional or posttranslational activation of pro‐apoptotic BH3‐only proteins. Their subsequent sequestration of the pro‐survival Bcl‐2 family members relieves Bcl‐2 mediated inhibition of Bax and Bak and leads to Bax‐ and Bak‐induced loss in mitochondrial membrane integrity. Cytochrome c is released into the cytosol, and together with Apaf‐1, forms the caspase‐9 activating apoptosome complex. IAP antagonists, such Smac, are released from the mitochondria concurrently with cytochrome c to antagonize XIAP inhibition of caspase activity. Caspase‐9‐mediated activation of the effector caspases, caspases‐3 and caspases‐7, results in apoptosis.

Figure 2.

Models for death receptor signalling. TNFR1 activation results in the formation of an NFκB inducing complex (complex I) at the cell surface. TRAF2 and/or cIAP1 and cIAP2 ubiquitinate RIP1, and together with TRAF2 ubiquitination, this leads to the recruitment and activation of an IKK kinase complex. IKK‐mediated phosphorylation of IκB results in its degradation by the proteasome, allowing the NFκB heterodimers, p65/p50, to translocate to the nucleus and initiate gene transcription. Following TRADD dissociation from TNFR1, FADD and caspase‐8 are recruited to form a secondary complex, complex II, which results in cell death in the absence of NFκB function (see text). In contrast to TNFR1, Fas and TRAIL receptors initiate cell death complexes (complex I) at the plasma membrane. Although, TRAIL‐induced NFκB has been reported to occur following FADD and caspase‐8 dissociation from TRAILR1 and recruitment of RIP1, TRAF2 and IKK to form a cytoplasmic complex II, how Fas signals NFκB remains uncertain.

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Further Reading

Adams JM and Cory S (2007) Bcl‐2‐regulated apoptosis: mechanism and therapeutic potential. Current Opinion in Immunology 19: 488–496.

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Strasser A, Jost PJ and Nagata S (2009) The many roles of FAS receptor signaling in the immune system. Immunity 30: 180–192.

Vazquez A, Bond EE, Levine AJ and Bond GL (2008) The genetics of the p53 pathway, apoptosis and cancer therapy. Nature Reviews. Drug Discovery 7: 979–987.

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Vince, James E, and Silke, John(Sep 2009) Apoptosis: Regulatory Genes and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006044.pub2]