The Siren's Song: This Death That Makes Life Live

Abstract

Individual cells can divide (mitosis), specialize (differentiate) or undergo programmed cell death (apoptosis). The balance between these processes ensures that the number of cells in an organism remains essentially constant. In the past 30 years, the molecular mechanisms of cell death have been identified (caspases, Bcl‐2 family, death receptors and apoptosome), with their clinical implications and therapeutic exploitation. Here, we review the entire process from a philosophical and historical viewpoint.

Key Concepts:

  • Besides dividing (mitosis) and specializing (differentiation), cells have an inherent, genetically programmed and biochemically regulated molecular mechanism of programmed cell death.

  • Life is a result of a continuous suppression of this death mechanism. In fact this programmed cell death pathway is always ready, and can be activated within minutes by membrane (cell to cell communication), cytosolic (stress) or nuclear (DNA damage) events.

  • Different forms of programmed cell death have been described, requiring different molecular subroutines, and with different morphological phenotypes and which occur in specific tissues. These include, among others and in addition to apoptosis, autophagy, keratinization, Wallerian degeneration and megakaryocytic fragmentation.

  • In contrast to apoptosis (a programmed cell death requiring caspase enzymatic activation, mitochondrial/apoptosome activation and Bcl‐2‐family regulation), necrosis causes the nonregulated release of intracellular molecules, resulting in inflammation. Indeed, apoptosis is often a silent, rapid death occurring in minutes and leaving no trace.

  • The pharmacologic regulation of cell death will affect all those diseases in which there is too little cell death (e.g. cancer and viral infections) or too much cell death (e.g. neurodegeneration and AIDS). Therefore the identification of the molecular events underlying apoptosis could lead to novel therapeutic approaches.

Keywords: apoptosis; cell death; caspases; Bcl‐2; C. elegans; P53

Figure 1.

Odysseus is tempted by the Sirens. Homer first describes the death wish of the Siren's song, and the way Odysseus resists to survive. Indeed, Homer describes death (point 1 on the right) and two survival mechanisms (points 2 and 3). Similarly Orpheus (point 4) counteracts death signals by playing survival signals with his song.

Figure 2.

Death and homeostasis. (a) The basic importance of cell death is in counteracting mitosis to regulate homeostasis of cell number in tissues as well as in the entire organism. Consequently, unbalance of mitosis versus apoptosis results in pathologies with accumulation (e.g. cancer) or loss (e.g. neurodegeneration and AIDS) of cell numbers. (b) Physiological events such as immune responses require a tight regulation between death sensitivity and resistance.

Figure 3.

Mechanisms of cell death. Compared to living cells, apoptotic cells show cell shrinkage, smoothness of the cell membrane which remains intact, detachment of the nuclear membrane and condensation of chromatin (with fragmentation of DNA). The dead cell is recognized and phagocytosed by neighbouring cells, thus disappearing from the tissue. The entire process occurs within minutes. The genes involved can be distinguished into regulatory, effector killing and degradation and disposal genes, as indicated for the nematode and mammals. (* indicates families of proteins). The basic core mechanism of cell death requires a killer protease (ced‐3/caspases) always ready to act, which requires an activator (ced‐4/apaf‐1) which in turn is repressed by a regulator (ced‐9/Bcl‐2, related to mitochondria): ced‐9 —| ced‐4ced‐3 → death. This core mechanism is activated by an activator (Egl‐1/BH‐3), and followed by the rapid disposal of the dead corps: Elg‐1 —| ced‐9 —| ced‐4ced‐3 → death → phagocytosis.

Figure 4.

Scientific papers on cell death. A large number of scientific publications have focused on cell death. We might distinguish three phases, from scattered observations before 1965, when the original work in invertebrates and embryology described the phenomenon. From 1990, culminating with the 2002 Nobel Prize, the molecular events were identified. Recently, the detailed mechanisms have been investigated, whereas the clinical relevance, with its potential therapeutic exploitation is being explored. Inset, advancement occurs in steps, with pioneering explorative and controversial work followed by consolidation and refining research.

Figure 5.

Who, what, when. One minute history on cell death in ten points: who and what. In addition to preliminary scattered observations that nowadays we would recognize as cell death, we distinguish three arbitrary gross phases of research, definition of the phenomenon (1965–1988), definition of the molecular mechanism (1988–2002), refinement of the molecular pathways with their clinical relevance and therapeutic exploitation, see also (Vaux, ). In addition to these 10 points, we would like to stress two major events, (i) the launch of the first dedicated journal in 1994 (Cell Death & Differentiation by Nature‐Publishing‐Group with G Melino), and (ii) the award of the Nobel Prize for Medicine in 2002 (to S Brenner, J Sulston, HR Horvitz). Years are very indicative, used as quinquennium. Because of the severe space limitation we sincerely apologize to all those colleagues who could not be mentioned here, though we recognize their essential and pivotal contribution to the field.

Figure 6.

Molecular events of apoptosis. Cell death can be trigged by membrane (1 – death receptor, such as CD95), cytosolic (2 – metabolic stress signals) or nuclear (3 – DNA damage leading to p53 activation) events. Even though several pathways and cross‐talk are elicited by individual triggers, not shown, the signals converge on the mitochondrion/apoptosome to activate the downstream effector caspases, which dismantle the cell components. Mitochondria play a regulatory role by releasing activating factors, under the control of the Bcl‐2 proteins. The final regulation occurs at the apoptosomal level.

Figure 7.

Death as symbiosis or social regulation. Cell death could be conceived as a result of a social cross‐regulation between cells that need homoeostatic regulation in multicellular organisms, according to M Raff. Alternatively, it seems implicit in each individual cell to guarantee the ancestral symbiosis between mitochondria and nucleus in eukaryotic cells, according to JC Ameisen.

Figure 8.

Evolution of cell death. Molecular pathways seem to have evolved from specific biochemical routines and subroutines using specific genetic/proteic modules such as AP‐ATPase, Tir, BIR, NACHT and MATH domains which evolved and transferred across evolution. The insets show a simplified evolutionary tree of caspases and apaf‐1.

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Further Reading

Candi E, Schmidt R and Melino G (2005) The cornified envelope: a model of cell death in the skin. Nature Reviews Molecular and Cellular Biology 6(4): 328–340.

De Laurenzi V and Melino G (2000) Apoptosis. The little devil of death. Nature 406(6792): 135–136.

Melino G, De Laurenzi V and Vousden KH (2002) Friend or foe in tumorigenesis. Nature Reviews Cancer 2(8): 605–615.

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Melino, Gerry, Knight, Richard A, and Ameisen, Jean‐Claude(Dec 2009) The Siren's Song: This Death That Makes Life Live. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021560]