the TNF death receptor, which utilizes TRAF-2 to activate NF-κB and JNK survival
signals, while simultaneously recruiting and activating procaspases-8, and the decision
to execute cell death or proliferation is a complex interplay between these opposing
signals (Baud and Karin, 2001). Consistent with this model of caspase-12 activation,
when Irel is overexpressed, it autoactivates and potently induces cell death (Wang et
al., 1998a). However, in vivo Irel activation and caspase-12 cleavage occur with
different kinetics; caspase 12 cleavage is a late event often not observed until 16 -24
h after treatment, whereas Irel is activated immediately and has been shown to return
to an inactive, nonphosphorylated state within 5 h after application of ER stress
(Harding et al., 2000a). Clearly, the dependence of caspase-12 activation on Irel must
be tested in Ire1-null MEFs.
2.5
JNK
Several groups have reported that ER stress activates the cJUN NH 2 -terminal kinase
(JNK/SAPK) pathway (Srivastava et al., 1999; Urano et al., 2000b). JNK signaling
has been implicated in several forms of cell death, including UV irradiation, where
jnk-1,jnk-2-null MEFs are resistant to Cyt.c release and apoptosis (Tournier et al.,
2000). JNK may exert its effect by phosphorylating mitochondrial proteins (Aoki et
al., 2002), including Bcl-xL (Ito et al., 2001a). JNK activation can be detected within
1 h after treatment of cells with ER stress agents; therefore, it follows the kinetics of
Irel stimulation (Urano et al., 2000b). Ire1 overexpression induces JNK activation
(Urano et al., 2000b), which may be mediated through a TRAF2-dependent
recruitment of c-JUN NH 2 inhibitory kinase (JIK) (Yoneda et al., 2001). A TRAF-2
dominant-negative mutant, lacking its NH 2 activation domain, blocked Irel’s ability
to activate JNK, and Ire1α-/- MEFs do not activate JNK in response to thapsigargin
or tunicamycin, although the effect on subsequent apoptosis was not reported (Urano
et al., 2000b). However, interruption of JNK signaling prevented thapsigargin-
induced apoptosis in human jurkat cells, supporting a role for this signaling pathway
in ER stress-induced cell death (Srivastava et al., 1999).
2.6
c-Ablc-Abl is a tyrosine kinase implicated in several different forms of apoptosis depending
on its subcellular localization. Nuclear c-Abl has been shown to exert an effect on
DNA damage-induced apoptosis by activating the JNK pathway (Yuan et al., 1996;
1999). However, cytoplasmic c-Abl participates in the release of Cyt.c from the
mitochondria in response to reactive oxygen species (ROS) (Sun et al., 2000).
Recently, Ito et al. (2001b) convincingly demonstrated that in Rat-1 fibroblast
approximately 20% of c-Abl resides at the surface of the ER and functions in the ER
stress apoptosis network. After exposure to brefeldin A or A23187, ER localized c-
Abl becomes activated and translocates to mitochondria, concomitant with the release
THE ROLE OF THE ENDOPLASMIC RETICULUM IN APOPTOSIS 103