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Article |
IKKß programs to turn on the GADD45
–MKK4–JNK apoptotic cascade specifically via p50 NF-
B in arsenite response
Correspondence to Chuanshu Huang: chuanshu{at}env.med.nyu.edu
Cross talk between NF-
B and c-Jun N-terminal kinases (JNKs) has been implicated in the cell life and death decision under various stresses. Functional suppression of JNK activation by NF-B has recently been proposed as a key cellular survival mechanism and contributes to cancer cells escaping from apoptosis. We provide a novel scenario of the proapoptotic role of IB kinase ß (IKKß)–NF-B, which can act as the activator of the JNK pathway through the induction of GADD45
for triggering MKK4/JNK activation, in response to the stimulation of arsenite, a cancer therapeutic reagent. This effect of IKKß–NF-B is dependent on p50 but not the p65/relA NF-B subunit, which can increase the stability of GADD45 protein through suppressing its ubiquitination and proteasome-dependent degradation. IKKß–NF-B can therefore either activate or suppress the JNK cascade and consequently mediate pro- or antiapoptotic effects, depending on the manner of its induction. Furthermore, the NF-B p50 subunit can exert a novel regulatory function on protein modification independent of the classical NF-B transcriptional activity.
B kinase; MEF, mouse embryonic fibroblast; PARP, poly (ADP-ribose) polymerase; WT, wild-type.
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