Apoptosis: Molecular Mechanisms


Apoptosis is an intrinsic cell‐suicide programme, which ensures tissue homeostasis and safeguards the organism by eliminating unnecessary and unwanted cells, or cells that may constitute some form of danger to the organism, for example, tumour cells. Both during embryonic development and in the adult life of organisms, there is a need for a perfect balance between cell proliferation, differentiation and death. This balance is achieved, in part, through the precise regulation of apoptosis, which involves complex molecular events that ultimately activate, or prevent the activation of caspases (cysteine‐aspartic acid proteases). The activation of caspases is, in most cases, irreversible and represents the commitment to the cell death fate.

Key concepts:

  • Apoptosis is a genetically determined process, by which unwanted or unnecessary cells are eliminated from organisms.

  • Apoptosis is important in many biological contexts and deregulation of apoptosis may cause diseases, either in the case of insufficient apoptosis, which may contribute to excessive cell proliferation and cancer, or excessive apoptosis, which may cause degenerative and other disorders.

  • Many molecules and several signalling pathways contribute to the regulation of apoptosis; both intrinsic and extrinsic factors contribute to the regulation of apoptosis in a cell.

Keywords: apoptosis; caspases; IAPs; Bcl‐2; p53; c‐myc

Figure 1.

The intrinsic pathway in C. elegans, D. melanogaster and mammalians. The functional homologues are represented in boxes with the same colour. The activation of effector caspases occurs downstream of the activation of initiator caspases (CED‐3, Dronc and caspase‐9), which occurs on the formation of the apoptosome, a protein complex contaning CED‐4, Ark/Dark and Apaf‐1, and cytochrome c. In mammalians, the release of cytochrome c from mitochondria is a critical step for caspase activation, which is regulated by members for the Bcl‐2 family of proteins. In Drosophila, the importance of cytochrome c and Bcl‐2 family members (Debcl/Buffy) for apoptosome formation and caspase activation is still not clear. In C. elegans, CED‐4 directly activates CED‐3 with no apparent requirement of cytochrome c for this process to occur. The negative regulation of CED‐4 by CED‐9 is blocked by EGL‐1, a BH3‐only member of the Bcl‐2 family of proteins. IAPs (in mammalians) or Diap1 (in Drosophila) directly bind to caspases via their BIR (baculovirus inhibitory repeat) domains, to inhibit caspase activity. In Drosophila, reaper, grim and hid are three Diap1 antagonists, which directly bind Diap1 via the short N‐terminal peptide motif termed IBM (IAP‐binding motif) present in all three proteins, to release caspases from the negative interaction with Diap1. In mammalians, Smac/Diablo, HtrA2/Omi and ARTS (apoptosis‐related protein in the TGF‐signalling pathway) can function as antagonists of IAPs.

Figure 2.

The extrinsic pathway mediated by the FAS death receptor. FasL activates the Fas receptor by binding to the extracellular death receptor domain. Fas receptor also contains a cytoplasmic motif known as the death domain (DD), which is also found in the adaptor proteins FADD, TRADD and RIP. The DD of Fas binds to the DD of FADD, whereas FADD interacts with procaspase‐8/‐10, through another motif designated death effector domain (DED). The formation of this complex of FAS/FADD/procaspase‐8/‐10 (DISC complex) is required for the activation of caspases. Caspase‐8, in turn, cleaves both effector caspases and Bid, a proapoptotic member of the Bcl‐2 family of proteins. The processed Bid (tBid) activates Bax and Bak, members of the Bcl‐2 family that oligomerize to promote MOMP. tBid inhibits the function of the antiapoptotic members of the Bcl‐2 family (Bcl‐2 and Bcl‐xL), which normally prevent the oligomerization of Bax and Bak, inhibiting MOMP and apoptosis. MOMP allows the release of various proapoptotic mitochondrial proteins such as cytochrome c, Smac/Diablo and Htra2/Omi that further activate the apoptotic cascade. Cytochrome c induces the heptamerization of the cytosolic protein Apaf‐1, which binds procaspase‐9 to form the active apoptosome complex for cleavage of effector caspases, whereas SMAC and HtrA2 act as inhibitors of IAPs.

Figure 3.

Regulation of apoptosis by p53. Several stress conditions (DNA damage, hypoxia, oncogene activation, among others) lead to the transcriptional activation and an increase of the p53 protein levels. Activation of p53 promotes the transcriptional activation of many target genes involved in several cellular responses: apoptosis, cell cycle arrest, DNA repair and senescence. Under normal physiological conditions, the cytoplasmic p53 protein is maintained at low levels by MDM2 (an E3 ubiquitin ligase) that targets the p53 protein to ubiquitylation (Ub) and subsequent degradation by the proteosome. MDM2 is also a target of the nuclear p53 protein and MDM2 activity is counteracted by ARF in response to activation of oncogenes, such as c‐MYC. Inhibition of MDM2 allows p53 to accumulate, both in the nucleus and the cytoplasm. In the cytoplasm, p53 can interact with proteins of the Bcl‐2 family, being sequestered by Bcl‐xL at the mitochondrial outer membrane. PUMA, which is a transcriptional target of nuclear p53, is capable of disrupting the Bcl‐xL/p53 interaction, allowing p53 to interact with Bax/Bak proteins and inducing MOMP and the subsequent cascade of the mitochondrial apoptotic pathway (Green and Kroemer, ).



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Further Reading

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Cairrão, Fátima, and Domingos, Pedro M(Jan 2010) Apoptosis: Molecular Mechanisms. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001150.pub2]