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Modern Genetic Analysis Chapter 15. Regulation of Cell Number: Normal and Cancer Cells
The Machinery or Programmed Cell Death
The Apoptosis Pathway

In multicellular organisms, systems have evolved to eliminate damaged (and, hence, potentially harmful) cells through a self-destruct and disposal mechanism: programmed cell death, or apoptosis. This selfdestruct mechanism can be activated under many different circumstances. Regardless, the events in apoptosis seem to be the same (Figure 15-4). First, there is fragmentation of the DNA of the chromosomes, disruption of organelle structure, and loss of normal cell shape (apoptotic cells become spherical). Then, the cells break up into small cell fragments called apoptotic bodies that are phagocytosed (literally, eaten up) by motile scavenger cells.

In this section, we deal with the molecules responsible for carrying out apoptosis. In a later section, we shall consider how these responses are regulated within the cell.

Caspases

The engines of self-destruction are a series of enzymes called caspases (cysteine-containing aspartate-specific proteases) (see Genetics in Process 15-2). Proteases are enzymes that cleave other proteins. Each caspase is a protein rich in cysteines that, when activated, cleaves certain target proteins at specific aspartate residues in the target polypeptide chains. In a given organism, there is a family of caspase proteins, once again related to each other by polypeptide sequence; for example, in humans, 10 caspases have so far been identified. In normal cells, each caspase is present in an enzymatically inactive state, called the zymogen form. In general, a zymogen is an inactive precursor form of an enzyme that contains a longer polypeptide chain than does the final active enzyme. To turn the zymogen form into the active caspase, a part of the polypeptide is removed by enzyme cleavage (also known as proteolysis).

The current view is that there are two classes of caspases: initiators and executioners. Exactly how they are organized into a cascade of cleavage events is currently unclear. One scenario is that the initiator caspases are cleaved in response to activation signals coming from other classes of proteins. They in turn cleave one of the executioner caspases, which in turn cleaves another, and so forth.

MESSAGE
Programmed cell death is mediated by a sequential cascade of proteolysis events that activate enzymes targeted to destroy several key cellular components.

How do the executioner caspases carry out the cellu-lar sentence of death? In addition to activating other caspases, executioner caspases enzymatically cut the target proteins (Figure 15-5). One target is a "sequestering" protein that forms a complex with a DNA en-donuclease, thereby holding (sequestering) the endonuclease in the cytoplasm. On cleavage of the sequestering protein, the endonuclease is then free to enter the nucleus and chop up the cell's DNA. Another target is a protein that, when cut by the caspases, cleaves actin, a major component of the cytoskeleton, causing disruption of actin filaments and thus leading to a loss of normal cell shape. In similar fashion, all other aspects of the apoptosis phenotype are thought to be mediated by caspase-activated proteases.

© 1999 by W. H. Freeman and Company. All rights reserved.