1,2-Naphthoquinone disrupts the function of cAMP response element-binding protein through covalent modification.
1,2-Naphthoquinone (1,2-NQ) is an atmospheric contaminant with electrophilic properties that allow it to react readily with protein thiol groups such as those found on the cAMP response element-binding protein (CREB), a transcription factor with conserved cysteine residues that regulate DNA binding. In the present study, we explored the possibility that the interaction of 1,2-NQ with CREB will affect its activity, resulting in down-regulation of gene expression. With bovine aortic endothelial cells (BAECs) and a cell-free system, 1,2-NQ was found to covalently bind to CREB, and inhibit its DNA binding activity under conditions that were blocked by dithiothreitol. CRE-dependent luciferase activity and the down-regulation of Bcl-2 expression were suppressed by exposure of BAECs to 1,2-NQ. This phenomenon was not seen with the hydrocarbon, naphthalene, which lacks any electrophilic properties. The results indicate that CREB is a molecular target for 1,2-NQ which through irreversible binding, inhibits the function of this transcription factor.
Endo
Akiko
A
Department of Environmental Medicine, Doctoral Programs in Medical Sciences, Graduate School of Comprehensive Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Sumi
Daigo
D
Kumagai
Yoshito
Y
D000393:Air Pollutants / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D000393:Air Pollutants; D017362:Cyclic AMP Response Element-Binding Protein; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; C040756:1,2-naphthoquinone; D004247:DNA