Salient Features

Apoptosis can be initiated by physiological signals acting through specific receptors, or by damage to the nucleus, mitochondria, or other organelles (Fig. 4) (94).

Once initiated, apoptosis entails a series of biochemical steps that culminate in the controlled destruction of nuclear DNA and cross-linking of cellular constituents (98,99). These steps proceed in distinct phases: activation, commitment, and execution. Once cells enter the commitment phase, the execution phase and demise of the cell is inevitable. A prominent feature of all phases is a cascade in which a series of proteases, termed caspases, are sequentially activated by site-specific proteolysis (100). Caspases activated in the last steps of the cascade then specifically cleave cellular proteins. Most proteins that are cleaved by caspases are inactivated. Some proteins, however, are activated by caspase cleavage. A prominent feature of apoptosis is the intimate involvement of mitochondria (101,102). Mitochondria sense apoptotic signals by mechanisms that are only partially understood, and respond by releasing cytochrome c into the cytosol. These mitochond-rially derived molecules then initiate or reinforce signals that activate caspase cascades. The net result includes the activation of an endonuclease, inhibition of DNA repair, and activation of a cross-linking transglutaminase. During the last stages, cells shrink and disintegrate into small, cross-linked fragments, which are engulfed and degraded by macrophages or neighboring cells (Fig. 4).

Apoptosis is controlled by more than 100 proteins, which act in complex and interrelated pathways that are linked to other cellular process, such as proliferation and differentiation. It is beyond the scope of this chapter to provide a comprehensive description of the regulation and execution of apopto-sis. However, the salient features of apoptosis are shown in Figure 4.

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