Genetics of Apoptosis

(FADD-DN) in T cells (Newton et al., 1998; Zornig et al., 1998) have demonstrated
that FADD is essential for induction of apoptosis by CD95/Fas, TNFR1, and DR3.
However, a similar obligatory role of FADD in apoptosis signaling by Apo2L/TRAIL
or its death receptors has not been uniformly observed. Cells from FADD-deficient
mice remain susceptible to DR4-induced apoptosis (Yeh et al., 1998), and ectopic
expression of FADD-DN failed to block induction of apoptosis by either Apo2L/
TRAIL or overexpression of either DR4 or DR5 (Pan et al., 1997a; Sheridan et al.,
1997). While these studies suggest the existence of a FADD-independent mechanism
by which Apo2L/TRAIL activates caspase-8 (perhaps through another adapter), other
conflicting observations indicate that DR4–or DR5-induced apoptosis can be
inhibited by transfection of FADD-DN (Walczak et al., 1997). The physiologic role
of FADD is further supported by Apo2L/TRAIL-dependent recruitment of FADD

Figure 2. Schematic representation of the molecular mechanisms and regulation

of death receptor-induced apoptosis.

Ligand-induced trimerization of death receptors facilitates binding of the adapter

protein, FADD/MORT1, through homotypic interactions between their DDs.

FADD carries a death-effector domain (DED), which interacts with the analogous

DED motifs found in procaspase-8/FLICE. FADD-dependent recruitment of

multiple procaspase-8 molecules to the receptor:FADD scaffold results in

autocatalytic cleavage and cross-activation. Caspase-8 triggers proteolytic activation

of caspase-3. Caspase-8 also cleaves and activates BID. The active truncated form

of BID (tBID) translocates to the outer mitochondrial membrane, where it binds

BAX or BAK. tBID-induced homoligomerization of BAX or BAK results leads to

DEATH RECEPTORS IN APOPTOSIS 5