Title: Both IKKalpha and IKKbeta are implicated in the arsenite-induced AP-1 transactivation correlating with cell apoptosis through NF-kappaB activity-independent manner.
Authors: Song, Lun; Li, Jingxia; Hu, Meiru; Huang, Chuanshu
Published In Exp Cell Res, (2008 Jul 1)
Abstract: Arsenite has been well-proved to act as both an environmental carcinogen as well as a tumor therapeutic agent. AP-1 is one of the transcription factors that can be induced upon arsenite stimulation. However, the study on the mechanism and the function of the arsenite-induced AP-1 transactivation remains far complete. Here we demonstrated that high dose of arsenite induced apoptotic response in mouse fibroblasts correlating with AP-1 transactivation, which events were mediated by both IKKalpha and IKKbeta, two major protein kinases responsible for NF-kappaB activation. In addition, the regulatory effect of IKKs on the arsenite-induced AP-1 activation was delivered by sequential induction of GADD45alpha expression and the activation of MAPKK (MKK3/4/6) and MAPK (JNK and p38K)-dependent pathways. We further provided evidence that p50, but not p65 subunit of NF-kappaB, was involved in GADD45alpha induction and the subsequent MAPKK/MAPK/AP-1 activation under arsenite exposure, while functional NF-kappaB induced by arsenite stimulation consisted of p65 but not of p50 subunit. Therefore, we concluded that both IKKalpha and IKKbeta can mediate arsenite-induced AP-1 transactivation through NF-kappaB activity-independent manner.
PubMed ID: 18508047
MeSH Terms: Animals; Apoptosis/physiology*; Arsenites/pharmacology*; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Cells, Cultured; Enzyme Activation; Fibroblasts/cytology; Fibroblasts/drug effects*; Fibroblasts/physiology; I-kappa B Kinase/genetics; I-kappa B Kinase/metabolism*; MAP Kinase Signaling System/physiology; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases/metabolism; NF-kappa B/metabolism*; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Protein Subunits/genetics; Protein Subunits/metabolism; Transcription Factor AP-1/metabolism*; Transcriptional Activation