JunB and JunD regulate human heme oxygenase-1 gene expression in renal epithelial cells.
Heme oxygenase-1 is a highly inducible gene, the product of which catalyzes breakdown of the prooxidant heme. The purpose of this study was to investigate the regulation of the human heme oxygenase-1 gene in renal epithelial cells. DNase I hyper-sensitivity studies identified three distal sites (HS-2, -3, and -4) corresponding to approximately -4.0, -7.2, and -9.2 kb, respectively, of the heme oxygenase-1 promoter in addition to one proximal region, HS-1, which we have shown previously to be an E box. In vivo dimethyl sulfate footprinting of the HS-2 region revealed six individual protected guanines. Two mutations within HS-2 combined with a third mutation of the proximal E box abolished hemin- and cadmium-driven heme oxygenase-1 promoter activation, suggesting that these three sites synergized for maximal heme oxygenase-1 induction. Jun proteins bound to the antioxidant response element in the HS-2 region in vitro and associated with the heme oxygenase-1 promoter in vivo. JunB and JunD contribute opposing effects; JunB activated whereas JunD repressed heme oxygenase-1 expression in human renal epithelial cells, results that were corroborated in junB(-)(/)(-) and junD(-)(/)(-) cells. We propose that heme oxygenase-1 induction is controlled by a dynamic interplay of regulatory proteins, and we provide new insights into the molecular control of the human heme oxygenase-1 gene.
Hock
Thomas D
TD
Department of Medicine, Nephrology Research and Training Center, University of Birmingham, Birmingham, Alabama 35294, USA.
Liby
Karen
K
Wright
Marcienne M
MM
McConnell
Sean
S
Schorpp-Kistner
Marina
M
Ryan
Thomas M
TM
Agarwal
Anupam
A
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D024721:E-Box Elements; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*
D016755:Proto-Oncogene Proteins c-jun; D051547:Heme Oxygenase-1