In adult tissues that are neither growing nor shrinking, cell death and cell division must be tightly regulated to ensure that they are exactly in balance. If part of the liver is removed in an adult rat, for example, liver cell proliferation increases to make up the loss. Conversely, if a rat is treated with the drug phenobarbital— which stimulates liver cell division (and thereby liver enlargement)—and then the phenobarbital treatment is stopped, apoptosis in the liver greatly increases until the liver has returned to its original size, usually within a week or so. Thus, the liver is kept at a constant size through the regulation of both the cell death rate and the cell birth rate. The control mechanisms responsible for such regulation are largely unknown.
Animal cells can recognize damage in their various organelles and, if the damage is great enough, they can kill themselves by undergoing apoptosis. An important example is DNA damage, which can produce cancer-promoting mutations if not repaired. Cells have various ways of detecting DNA damage, and undergo apoptosis if they cannot repair it.
Apoptosis is triggered by members of a family of specialized intracellular proteases, which cleave specific sequences in numerous proteins inside the cell, thereby bringing about the dramatic changes that lead to cell death and engulfment. These proteases have a cysteine at their active site and cleave their target proteins at specific aspartic acids; they are therefore called caspases (c for cysteine and asp for aspartic acid). Caspases are synthesized in the cell as inactive precursors and are activated only during apoptosis. There are two major classes of apoptotic caspases: initiator caspases and executioner caspases.
Figure 18–1 Two distinct forms of cell death. these electron micrographs show cells that have died by apoptosis (A and
B) or by necrosis (C). the cells in (A) and (C) died in a culture dish, whereas the cell in (B) died in a developing tissue and has been engulfed by a phagocytic cell. Note that the cells in (A) and (B) have condensed but seem relatively intact, whereas the cell in (C) seems to have exploded. the large vacuoles visible in the cytoplasm of the cell in (A) are a variable feature of apoptosis. (Courtesy of Julia Burne.)
Figure 18–2 Sculpting the digits in the developing mouse paw by apoptosis.
the paw in this mouse fetus has been stained with a dye that specifically labels cells that have undergone apoptosis. the apoptotic cells appear as bright green dots between the developing digits.
the interdigital cell death has eliminated the tissue between the developing digits, as seen one day later, when there are very few apoptotic cells. (From W. Wood et al., Development 127:5245–5252, 2000. With permission from the Company of Biologists.) initiator caspase (caspases 8,9)
DIMERIZATION, ACTIVATION, AND CLEAVAGE executioner caspase (caspases 3,6,7) CLEAVAGE OF MULTIPLE SUBSTRATES
Initiator caspases, as their name implies, begin the apoptotic process. They normally exist as inactive, soluble monomers in the cytosol. An apoptotic signal triggers the assembly of large protein platforms that bring multiple initiator caspases together into large complexes. Within these complexes, pairs of caspases associate to form dimers, resulting in protease activation (Figure 18–3). Each caspase in the dimer then cleaves its partner at a specific site in the protease domain, which stabilizes the active complex and is required for the proper function of the enzyme in the cell.