Genetics of Apoptosis

overexpression of Bcl-2 or Bcl-xL exhibit extended cell survival and pathologic cellular
accumulation in the targeted tissues (Strasser et al., 2000). Conversely, mice lacking
Bcl-2 show premature demise of mature lymphocytes, while Bcl-x-deficiency results
in increased neuronal apoptosis and embryonic lethality (Motoyama et al., 1995;
Middleton et al., 2000).
In addition to death by neglect from loss of trophic survival signals, developmental
cell death may also require activation of death receptor-induced caspase-8-mediated
signaling pathways. The principal effects of the loss of TNF, CD95 or their cognate
ligands are on the immune system (Yeh et al., 1999). However, death receptor-
induced apoptosis may also be important in other systems. Apoptosis of spinal motor
neurons in response to trophic factor withdrawal is inhibited by an antagonistic anti-
CD95 antibody (Raoul et al., 1999). Caspase-8-/-mice suffer embryonic lethality after
day 11.5, with poorly developed heart musculature and abnormal accumulation of
erythrocytes in the liver, lung, lens, and mesenchyma (Varfolomeev et al., 1998).
FADD-/- embryos die at the same stage of development with similar cardiac
abnormalities, and FADD-/- T cells exhibit impaired antigen-induced proliferation
(Zhang et al., 1998). The absence of obvious developmental defects in most tissues
in mice lacking specific TNF-R or TNF family members, and the focal failure of
specific tissues in FADD-/- or caspase-8-/- mice are indicative of functional overlap
and redundancy within the TNF-R/TNF-family and between the mitochondrial and
death receptor-induced signaling pathways.

7.

Death receptor-induced apoptosis of tumor cells

7.1

Role of death receptors/ligands in tumor surveillance

Death receptor-ligand interactions may serve a critical physiologic function in tumor
surveillance (Kashii et al., 1999). NK cells play a pivotal role in the control of tumor
metastasis (Talmadge et al., 1980; Karre et al., 1986). Freshly isolated murine liver
NK cells, but not natural killer T cells or ordinary T cells, constitutively express cell-
surface Apo2L/TRAIL, which, together with perforin and Fas ligand (FasL), mediate
NK cell-dependent suppression of experimental liver metastasis of tumor cells
(Takeda et al., 2001). Administration of neutralizing monoclonal antibodies against
either Apo2L/TRAIL or FasL significantly increases hepatic metastases of several
tumor cell lines. While inhibition of perforin-mediated killing also inhibits NK-
mediated cytotoxicity (Smyth et al., 1999), complete inhibition is achieved only with
the combination of anti-TRAIL and anti-FasL antagonistic antibodies (Takeda et al.,
2001). Endogenously produced interferon-γ plays a critical role in inducing Apo2L/
TRAIL expression on NK cells and T cells (Kayagaki et al., 1999). These findings
suggest that Apo2L/TRAIL and FasL may contribute to the natural suppression of

26 GENETICS OF APOPTOSIS