Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death:- Apoptosis Is Programmed Cell Suicide
Many cells can precisely control the time of their own death by the process of programmed cell death, or apoptosis (app-a-toe-sis; from the Greek for “drop ping off,” as in leaves dropping in the fall). In the development of an embryo, for example, some cells must die. Carving fingers from stubby limb buds requires the precisely timed death of cells between developing fin ger bones. During development of the nematode Caenorhabditis elegans from a fertilized egg, exactly 131 cells (of a total of 1,090 somatic cells in the embryo) must undergo programmed death in order to con struct the adult body.
Apoptosis also has roles in processes other than development. When an antibody-producing cell begins to make antibodies against an antigen normally present in the body, that cell undergoes programmed death in the thymus gland—an essential mechanism for eliminating anti-self-antibodies. The monthly sloughing of cells of the uterine wall (menstruation) is another case of apoptosis mediating normal cell death. Sometimes cell suicide is not programmed but occurs in response to bio logical circumstances that threaten the rest of the organism. For example, a virus-infected cell that dies before completion of the infection cycle prevents spread of the virus to nearby cells. Severe stresses such as heat, hyperosmolarity, UV light, and gamma irradiation also trigger cell suicide; presumably the organism is better off with aberrant cells dead.
The regulatory mechanisms that trigger apoptosis involve some of the same proteins that regulate the cell cycle. The signal for suicide often comes from outside, through a surface receptor. Tumor necrosis factor (TNF), produced by cells of the immune system, inter acts with cells through specific TNF receptors. These receptors have TNF-binding sites on the outer face of the plasma membrane and a “death domain” of about 80 amino acid residues that passes the self-destruct signal through the membrane to cytosolic proteins such as TRADD (TNF receptor-associated death domain) (Fig. 12–50). Another receptor, Fas, has a similar death domain that allows it to interact with the cytosolic protein FADD (Fas-associated death domain), which activates a cytosolic protease called caspase 8. This enzyme be longs to a family of proteases that participate in apoptosis; all are synthesized as inactive proenzymes, all have a critical Cys residue at the active site, and all hydrolyze their target proteins on the carboxyl-terminal side of specific Asp residues (hence the name caspase). When caspase 8, an “initiator” caspase, is activated by an apoptotic signal carried through FADD, it further self-activates by cleaving its own proenzyme form. Mitochondria are one target of active caspase 8. The pro tease causes the release of certain proteins contained between the inner and outer mitochondrial membranes:
FIGURE 12–50 Initial events of apoptosis. Receptors in the plasma membrane (Fas, TNF-R1) receive signals from outside the cell (the Fas ligand or tumor necrosis factor (TNF), respectively). Activated receptors foster interaction between the “death domain” (an 80 amino acid sequence) in Fas or TNF-R1 and a similar death domain in the cytosolic proteins FADD or TRADD. FADD activates a cytosolic pro tease, caspase 8, that proteolytically activates other cellular proteases. TRADD also activates proteases. The resulting proteolysis is a primary factor in cell death.
cytochrome c and several “effector” caspases. Cytochrome c binds to the proenzyme form of the effector enzyme caspase 9 and stimulates its proteolytic activation. The activated caspase 9 in turn catalyzes wholesale destruction of cellular proteins—a major cause of apoptotic cell death. One specific target of caspase action is a caspase-activated deoxyribonuclease. In apoptosis, the monomeric products of protein and DNA degradation (amino acids and nucleotides) are released in a controlled process that allows them to be taken up and reused by neighboring cells. Apoptosis thus allows the organism to eliminate a cell without wasting its components.
