Both IKKalpha and IKKbeta are implicated in the arsenite-induced AP-1 transactivation correlating with cell apoptosis through NF-kappaB activity-independent manner.
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.
Song
Lun
L
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA. lunsong@yahoo.com
Li
Jingxia
J
Hu
Meiru
M
Huang
Chuanshu
C
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018053:Arsenites / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D000097642:GADD45 Proteins
D018053:Arsenites; D018797:Cell Cycle Proteins; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009687:Nuclear Proteins; D021122:Protein Subunits; D018808:Transcription Factor AP-1; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C015001:arsenite