(CD95L) is, however, restricted to cytotoxic T cells, NK cells, and antigen presenting
cells (APCs) (Li, J.H. et al., 1998).
Akin to TNFR1 and CD95, the death receptors for Apo2L/TRAIL (DR4/TRAIL-
R1 and DR5/TRAIL-R2) are broadly expressed in most organ systems (Golstein,
1997; Ashkenazi and Dixit, 1998). However, unlike the restricted pattern of TNF
and CD95L expression in immune activated T cells and APCs, Apo2L/TRAIL
mRNA is expressed constitutively in many tissues, and transcript levels increase upon
stimulation in peripheral blood T cells (Screaton et al., 1997a; Jeremias et al., 1998;
Martinez-Lorenzo et al., 1998). Since several tissues constitutively express both
Apo2L and its death receptors, normal cells must employ mechanisms to protect
themselves from autocrine or paracrine Apo2L-DR4/DR5 interactions. One such
line of defense is provided by expression of a set of decoy receptors (DcRs). DcR1
(also called TRAIL-R3, TRID, or LIT) is a glycosyl phosphatidylinositol (GPI)-
anchored cell-surface protein that is structurally related to DR4 and DR5, but lacks
a cytoplasmic tail (Degli-Esposti et al., 1997b; Pan et al., 1997b; MacFarlane et al.,
1997; Mongkolsapaya et al., 1998; Schneider et al., 1997; Sheridan et al., 1997).
DcR2 (also called TRAIL-R4 or TRUNDD) also resembles DR4 and DR5, but has
a truncated cytoplasmic DD that is only a third as long as that of functional DDs
that are capable of transducing apoptotic signals (Degli-Esposti et al., 1997a; Marsters
et al., 1997; Pan et al., 1998b). The extracellular domains of DcR1 and DcR2 compete
with DR4 and DR5 for binding to Apo2L/TRAIL, but cannot initiate death signals
in response to ligand engagement. Transfection of Apo2L-sensitive cells with either
DcR1 or DcR2 substantially reduces their sensitivity to Apo2L-induced apoptosis.
Deletion of the truncated cytoplasmic region of DcR2 does not affect its ability to
protect cells from Apo2L-induced death. Enzymatic cleavage of the GPI anchor also
results in the sensitization of DcR1-expressing cells to Apo2L-induced apoptosis.
These observations indicate that DcR1 and DcR2 may protect normal cells from
Apo2L by acting as ‘decoys’ that compete with TRAIL-R1/TRAIL-R2 for their shared
ligand. The expression of decoy receptors provides a potential molecular basis for the
relative resistance of normal cells to TRAIL/Apo2L-induced death. In support of this
notion, resting peripheral T cells (that resist Apo2L) exhibit an elevation of DR5
(Screaton et al., 1997a) and concomitant reduction of DcR1 levels (Mongkolsapaya
et al., 1998) when they acquire an Apo2L-sensitive phenotype upon activation by
interleukin-2 (Martinez-Lorenzo et al., 1998). However, many tumor cell lines
express high levels of decoy receptors, yet remain susceptible to Apo2L-induced death
(Griffith and Lynch, 1998). Therefore, it is likely that the susceptibility of cells to
Apo2L-induced apoptosis must involve additional regulatory mechanisms beyond
the ratio of death and decoy receptors.
A third decoy receptor, DcR3, is a secreted soluble protein the binds to CD95L
(Pitti et al., 1998). DcR3 competitively inhibits the interaction of CD95 with
CD95L, and overexpression of DcR3 inhibits CD95-induced apoptosis (Pitti et al.,
1998). DcR3 mRNA is expressed in the spleen, colon, and lung. While its physiologic
role remains unclear, the frequent amplification of the DcR3 gene in primary lung
and colon cancers may protect tumor cells from CD95L-induced death.
10 GENETICS OF APOPTOSIS