Genetics of Apoptosis

(Barry) #1

of these death-signaling pathways. We also review the physiologic role of death
receptors and describe pathologic conditions that result from a failure or deregulation
of their activity. Finally, we highlight the enormous promise of targeting death
receptors or their regulatory circuits for treatment of human disease.


2.

Death receptors and ligands

Death receptors are cell-surface receptors that trigger death signals following
engagement with their cognate ‘death ligands’ (Ashkenazi and Dixit, 1998). Death
receptor-transduced signals play an instrumental role in ‘instructive apoptosis’, a
mechanism that has evolved to enable the deletion of cells in higher metazoans. Death
receptors belong to the tumor necrosis factor receptor (TNFR) gene superfamily,
whose members have cysteine-rich extracellular domains (CRDs) in their amino
terminal region (Smith et al., 1994). The death receptors constitute a subgroup of
this family that also possess a homologous cytoplasmic sequence termed the ‘death
domain’ (DD) (Figure 1) (Brakebusch et al., 1992; Itoh and Nagata, 1993). The best-
characterized death receptors are TNFR1 (also termed p55 or CD120a) (Smith et
al., 1994), CD95 (also called Fas or Apo1) (Nagata, 1997), avian CAR1, death
receptor 3 (DR3; also called Apo3, WSL-1, TRAMP, or LARD) (Chinnaiyan et al.,
1996b; Kitson et al., 1996; Marsters et al., 1996; Bodmer et al., 1997; Screaton et al.,
1997b), TRAIL-Rl (also called DR4) (Pan et al., 1997b), TRAIL-R2 (also called
DR5, Apo2, TRICK2, or KILLER) (Pan et al., 1997a; Screaton et al., 1997a;
Sheridan et al., 1997; Walczak et al., 1997; Wu, G.S. et al., 1997), and DR6 (Pan et
al., 1998a). These receptors are activated by ligands of the TNF gene superfamily;
TNFR1 is ligated by TNF and lymphotoxin a, CD95 is bound by CD95L (FasL)
(Nagata, 1997), DR3 interacts with Apo3 ligand (Apo3L, also called TWEAK)
(Chicheportiche et al., 1997; Marsters et al., 1998), and TRAIL-Rl and TRAIL-R2
are engaged by Apo2 ligand (Apo2L, which is also called TNF-related apoptosis-
inducing ligand [TRAIL]) (Wiley et al., 1995; Pitti et al., 1996).


3.

Induction of apoptosis by death receptors

3.1

The molecular machinery of cell death—caspases

The molecular machinery of cell death comprises an evolutionarily conserved family
of cysteine aspartate proteases (caspases) that execute cell disassembly via cleavage of
critical substrates that maintain cytoskeletal and DNA integrity (Earnshaw et al.,
1999). Caspases recognize specific tetrapeptide motifs in their target proteins and
cleave their substrates at Asp-Xxx bonds (after aspartic acid residues) (Thornberry et
al., 1997). At least 14 caspases and more than 100 substrates have been identified


2 GENETICS OF APOPTOSIS

Free download pdf