IKK   β    programs to turn on the GADD45α/MKK4/JNKs apoptotic cascade specifically via p50 NF-κB in arsenite response    Free

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Crosstalk between NF-κB and JNKs has been implicated in the cell life and death decision under various stresses. Functional suppression of JNKs activation by NF-κB has been recently proposed as a key cellular survival mechanism and contributes to cancer cells escaping from apoptosis.Here, we provide a novel scenario of the pro-apoptotic role of IKKβ/NF-κB, which can act as the activator of the JNKs pathway through the induction of GADD45α for triggering MKK4/JNKs activation, in response to the stimulation of arsenite, a cancer therapeutic reagent. This effect of IKKβ/NF-κB is dependent on p50, but not p65/relA NF-κB subunit, which can increase the stability of GADD45α protein through suppressing its ubiquitination and proteasome-dependent degradation.IKKβ/NF-κB can therefore either activate or suppress the JNKs cascade and consequently mediate pro- or anti-apoptotic effects dependent upon the manner of its induction. Furthermore, the NF-κB p50 subunit can exert a novel regulatory function on protein modification independent of the classical NF-κB transcriptional activity.