Apoptosis
or programmed cell death is induced in cells by a group
of death domain containing receptors. Binding of ligand
to these receptors sends signals that activate members
of the caspase family of proteases. The signals ultimately
cause degradation of chromosomal DNA by activating DNase.
TRAIL (TNF related apoptosis induced ligand) or Apo 2L
initiates apoptosis of tumor cells by binding to either
of its receptors, DR4 or DR5. These receptors consist of
an extracellular TRAIL binding domain and a cytoplasmic "death
domain". In addition, two decoy receptors for TRAIL
have also been identified. These receptors, designated
DcR1 and DcR2, lack the death domain. Binding of TRAIL
to either of these receptors, therefore, does not transmit
the death signal. Thus, these receptors represent a novel
way of regulating cell sensitivity to a pro-apoptotic cytokine
at the cell surface. TRAIL is expressed predominantly in
spleen, lung, and prostate but also in many other tissues.
DR4
is expressed in most of human tissues including spleen,
peripheral blood leukocytes, small intestine and thymus.
Like TNFR1, Fas and DR3, DR4 mediates apoptosis and
NF kB activation in many tissues and cells. The predicted
468-amino acid DR4 protein contains a putative signal
peptide, 2 cysteine-rich pseudorepeats resembling corresponding
regions in TNFR1, DR3, and FAS, a transmembrane domain,
and an intracellular death domain. The death domain
of
DR4 shares 28% and 30% identity with those of DR3 and
TNFR1,
respectively. As with FAS, TNFR1, and DR3, overexpression
of DR4 induced apoptosis. However, unlike the other
3 death receptors, DR4 did not use FADD to transmit the
death
signal,
suggesting the use of distinct proximal signaling machinery. |
