Genetics of Apoptosis

In certain cell types, inhibition of NF-κB by a degradation-resistant mutant of IκBα
results in increased Bax promoter activity and expression of BAX. Although the Bax
promoter has a κB site that binds Rel proteins, it is not required for NF-κB-mediated
inhibition of BAX expression. Therefore, NF-κB may increase BAX expression via
an indirect mechanism. One possibility is that NF-κB may repress stimulation of the
Bax promoter by interfering with the function of the p53 tumor suppressor gene.
While the precise molecular mechanism remains unclear, the reduced expression of
BAX may contribute to the resistance of cells with constitutive activation of NF-κB
to death receptor-induced apoptosis. As discussed earlier, targeted loss of the Bax gene
renders cancer cells resistant to CD95L, TNF-α, and Apo2L/ TRAIL-induced
apoptosis Deng et al., 2002; LeBlanc et al., 2002; Ravi and Bedi, 2002). Since NF-
κB is constitutively activated by diverse genetic aberrations in human cancers, NF-
κB-mediated repression of BAX may play a role in protecting tumor cells from death
receptor-ligand interactions (Ravi and Bedi, 2002).
Finally, NF-κB also induces expression of a JNK inhibitor (De Smaele et al., 2001;
Javelaud and Besancon, 2001; Tang et al., 2001a). TNF-α-induced activation of
JNK occurs transiently in normal cells but is increased and prolonged in IKKβ-or
RelA-deficient cells (Tang et al., 2001a). Although the identity of the NF-κB-induced
JNK inhibitor remains unclear, the identified candidates include XIAP and the
GADD45β protein (De Smaele et al., 2001; Tang et al., 2001a). Ectopic expression
of GADD45β abrogates TNF-α-induced activation of JNK and rescues RelA-/- cells
from TNF-α-induced apoptosis. Although the suppression of JNK may contribute
to the antiapoptotic function of NF-κB, JNK is not an essential mediator of death
receptor-induced apoptosis.
These observations suggest that NF-κB inhibits death receptor-induced apoptosis
by concomitant induction of multiple survival genes as well as repression or
inactivation of proapoptotic genes.

4.7

The dynamic balance between death receptors and apoptosis-

inhibitors—a tug-of-war that determines cell fate

The activation of caspases by death receptor-induced signals is held in check by the
antiapoptotic proteins described above. While this serves to prevent unscheduled or
uncontrolled cell death, the induction of apoptosis in response to physiologic death
signals requires mechanisms to circumvent or overcome these antiapoptotic proteins.
Without such mechanisms, the failure of death receptor-induced apoptosis would
disrupt homeostasis and result in immune and neoplastic disorders. The dynamic
balance between the antagonistic functions of death receptors and anti-apoptotic
proteins ensures that death receptor-induced apoptosis is allowed to proceed in a
signal-dependent, scheduled, and controlled fashion. The molecular mechanisms by
which this balance is tipped in favor of instructive apoptosis involves signal-induced
expression of death receptors and caspase-mediated proteolysis of many of the key
proteins that inhibit death receptor-induced apoptosis.

18 GENETICS OF APOPTOSIS