Page 5 - Academic Press Encyclopedia of Physical Science and Technology 3rd Molecular Biology

P1: GQQ Revised Pages
Encyclopedia of Physical Science and Technology EN002G-90 May 17, 2001 20:42

Cell Death (Apoptosis) 543

immature and autoreactive T cells, Wolffian and Mullerian a death domain (DD) that is required for transducing
duct regression during sexual development, tumor regres- apoptotic signals to cells. Six DD-containing death re-
sion, and in elimination of virus-infected cells. Further- ceptors, namely Fas/Apo1/CD95, type I TNF recep-
more, it has been suggested that apoptosis occurs in many tor (TNFRI), DR3/Apo3/WSL-1/TRAMP, DR4/TRAIL-
diseases such as cancer, fulminant hepatitis, acquired im- R1 (TNF-related apoptosis-inducing ligand receptor-1),
mune deficiency syndrome (AIDS), diabetes mellitus, and DR5/TRAIL-R2/TRICK2/KILLER and DR6 have been
neurodegenerative disorders such as Alzheimer’s disease identified so far. In addition, there are DD-less death re-
and prion disease. ceptors such as type II TNF receptor (TNFRII), CD27,
Growth and differentiation of cells are strictly regulated CD30, CD40, and lymphotoxin-β receptor. Among these,
by factors such as cytokines and low-molecular-weight TNFRII, CD27, and CD30 induce the expression of both
compounds such as steroid hormones. These factors are TNF and TNFRI by their cognate ligands, and subsequent
generally bound to the corresponding receptors in order to induction of apoptosis appears to occur.
transduce the appropriate cell signals, to promote growth On the other hand, death factors are a member of
and differentiation. On the other hand, apoptotic cell death the TNF family and exist on the cell surface or as
is aggressively controlled by a number of polypeptides, soluble factors. Most death factors are synthesized as
so-called death factors exposed at the cell surface or cir- type II-membrane proteins and subjected to shedding by
culating in the body as soluble factors in some situations. membrane-associated metalloproteinases in order to gen-
Growth and differentiation factors act via transcriptional erate soluble forms of death factors. A well-established
regulation through the activation of a series of protein ki- mechanism for shedding of death factors is seen in the case
nases. On the other hand, death factors execute apoptosis of TNF. Membrane-bound TNF (memTNF) is cleaved at
through the activation of caspases, and many proteins es- theoutercellularmembranebyamembrane-spanningpro-
sentialforcellsurvivalaredegradedbytheseactivatedcas- tease, so-called TNF α-converting enzyme (TACE), which
pases. It is currently believed that apoptotic death is due to is a member of metalloproteinase-disintegrin (ADAM)
the degradation of many functional proteins by caspases. family. memTNF is superior to soluble TNF (sTNF) in
Cell-free systems for the study of apoptosis have been activating TNFRII in various cellular responses, includ-
established and facilitate our understanding of the under- ing T-cell proliferation, inflammation, and cytotoxicity.
lying molecular mechanisms. Several factors involved in These results imply that memTNF regulates cellular re-
apoptotic pathways have been identified and part of these sponses via restricted cell-to-cell interaction under physi-
pathways has been revealed by biochemical approaches ological conditions and that sTNF may attenuate TNFRII-
based on cell-free apoptosis system. Regulatory mecha- mediated responses. The shedding mechanism for other
nisms for apoptosis include: the CED-3/caspase family death factors may be similar to that for TNF. Like in shed-
proteases and CED-4/Apaf-1 family which act as execu- ding of TNF, the membrane form of Fas ligand (mem-
tors of apoptosis; CED-9/Bcl-2 family (including anti- FasL) is also cleaved by an unknown metalloproteinase
apoptotic and pro-apoptotic factors) which act as regu- other than TACE present on the plasma membranes. In
lators of apoptosis, and many factors which contribute addition, the soluble form of Fas ligand (sFasL) inhibits
to apoptotic morphological changes have been identified. mFasL-mediated apoptosis in human peripheral blood T
Here, I shall focus on the currently proposed molecular lymphocytes in vitro.
mechanisms of death receptor activity and caspase activa- It is believed that death receptors are activated by
tion. Moreover, I will also discuss the DNase responsible ligand-induced trimerization, as opposed to the activa-
for apoptotic DNA fragmentation, both in vitro and in tion of growth factor receptors, which occurs by dimer-
vivo, and finally the mechanism by which apoptotic cells ization. Most death factors, but not all, are present as
are cleared. trimers. X-ray structural analyses have revealed that TNF-
α, TNF-β, CD40L, and TRAIL are homotrimeric proteins.
Among these, TRAIL has unique characteristics. TRAIL
II. DEATH FACTORS AND requires a zinc ion for biological activity and selectively
THEIR RECEPTORS induces apoptosis in mouse tumor cells but not in nor-
mal cells. Moreover, administration of soluble TRAIL to
Many cells have death receptors on the surface of their mice implanted with human tumors causes effective re-
plasma membranes and apoptosis is triggered by their cog- duction of tumor size without any injury of normal tis-
nate ligands. Death receptors belong to the superfamily sues. These results suggest that TRAIL may be applicable
of tumor necrosis factor (TNF) receptors. Most consist as an anti-cancer drug. However, a recent paper reported
of a cysteine-rich extracellular domain, a membrane- that TRAIL induces apoptosis in human hepatocytes,
spanning domain, and a cytoplasmic domain containing indicating that substantial liver toxicity might result if