Title: IKKbeta programs to turn on the GADD45alpha-MKK4-JNK apoptotic cascade specifically via p50 NF-kappaB in arsenite response.
Authors: Song, Lun; Li, Jingxia; Zhang, Dongyun; Liu, Zheng-Gang; Ye, Jianping; Zhan, Qimin; Shen, Han-Ming; Whiteman, Matt; Huang, Chuanshu
Published In J Cell Biol, (2006 Nov 20)
Abstract: Cross talk between NF-kappaB 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-kappaB 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 IkappaB kinase beta (IKKbeta)-NF-kappaB, which can act as the activator of the JNK pathway through the induction of GADD45alpha for triggering MKK4/JNK activation, in response to the stimulation of arsenite, a cancer therapeutic reagent. This effect of IKKbeta-NF-kappaB is dependent on p50 but not the p65/relA NF-kappaB subunit, which can increase the stability of GADD45alpha protein through suppressing its ubiquitination and proteasome-dependent degradation. IKKbeta-NF-kappaB 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-kappaB p50 subunit can exert a novel regulatory function on protein modification independent of the classical NF-kappaB transcriptional activity.
PubMed ID: 17116751
MeSH Terms: Animals; Apoptosis/drug effects*; Arsenites/pharmacology*; Cell Cycle Proteins/metabolism*; Enzyme Activation/drug effects; Fibroblasts/cytology; Fibroblasts/drug effects; I-kappa B Kinase/deficiency; I-kappa B Kinase/metabolism*; JNK Mitogen-Activated Protein Kinases/metabolism*; MAP Kinase Kinase 4/metabolism*; Mice; NF-kappa B p50 Subunit/deficiency; NF-kappa B p50 Subunit/metabolism*; Nuclear Proteins/metabolism*; Phosphorylation/drug effects; Proteasome Endopeptidase Complex/drug effects; Protein Processing, Post-Translational/drug effects; Signal Transduction/drug effects; Transcription Factor RelA/metabolism; Ubiquitin/metabolism; Up-Regulation/drug effects