Apoptosis by Death Factor

its activity when it is cleaved from the membrane. FurThere is an old Japanese saying that “Once we are in thermore, membrane-bound TNF is more active than the land of the living, we will eventually die.” This is true, soluble TNF in activating the type II TNF receptor (Grell not only for human beings, but also for the cells that et al., 1995). These results may indicate that FasL and constitute our bodies. By repeated cell division (mitosis) TNF work locally via cell–cell interactions under physioand differentiation, a fertilized egg produces billions of logical conditions and that the purpose of shedding TNF cells to create our bodies. During this process, many or FasL is to attenuate the process. surplus or harmful cells are generated, and they must The functional, soluble forms of TNFs as well as hube removed or killed (Jacobson et al., 1997 [this issue man FasL exist as trimers (Tanaka et al., 1997). It has of Cell]. For example, thymocytes that have failed to not yet been demonstrated whether membrane-bound rearrange their T cell–receptor gene, or whose T cell TNF or FasL are trimers. However, lymphotoxin b, a receptor may recognize their own tissues, must be elimimember of the TNF family, consists of a heterotrimer nated. The magnitude of the cell death is staggering: of one a (lymphotoxin-a, or TNFb) and two b chains more than 95% of thymocytes die in the thymus during (lymphotoxin-b) on the membrane (Androlewicz et al., maturation. Even in adults, senescent cells are removed 1992), suggesting that membrane-bound TNF and FasL and replaced by newly generated cells to maintain hohave the potential to form trimeric structures. X-ray meostasis. The cell death that occurs during emdiffraction analyses of TNFa and TNFb have indicated bryogenesis, metamorphosis, endocrine-dependent tisthat each monomer forms an elongated, antiparallel sue atrophy, and normal tissue turnover is “programmed b-pleated sheet sandwich with a jelly roll topology cell death,” mediated by a process termed “apoptosis.” (Jones et al., 1989). Amino acids conserved among Here, I focus on apoptosis controlled by cytokines. members of the TNF family are mainly within the b Two death factors, Fas ligand (FasL) or tumor necrosis strands. Computer-assisted modeling of FasL based on factor (TNF), bind to their receptors and induce the amino acid sequence suggests that FasL has a simiapoptosis, killing the cells within hours. In a classic defilar tertiary structure to TNFa and TNFb. nition of apoptosis, cells die by “suicide;” that is, cells The Fas and TNF Receptor Family programmed to die would do so autonomously. HowFas (also known as APO-1 or CD95), the receptor for ever, the identification of death factor–receptor pairs FasL, is a type I–membrane protein (Itoh et al., 1991; that regulate apoptosis indicates that apoptosis can Oehm et al., 1992) and a member of the TNF receptor also becontrolled by an external killer in someinstances. (TNFR) family, which includes two TNFRs (TNFR1 and