An internal enhancer regulates heme- and cadmium-mediated induction of human heme oxygenase-1.

Academic Article

Abstract

  • Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, releasing iron, carbon monoxide, and biliverdin. Induction of HO-1 is an adaptive and beneficial response in renal and nonrenal settings of tissue injury. The purpose of this study was to characterize the regulation of the human HO-1 gene in renal proximal tubule and aortic endothelial cells in response to heme and cadmium. Evaluation of multiple human HO-1 promoter-reporter constructs up to -9.1 kb demonstrated only a partial response to heme and cadmium. In an effort to mimic endogenous stimulus-dependent levels of HO-1 induction, we evaluated the entire 12.5 kb of the human HO-1 gene, including introns and exons, in conjunction with a -4.5-kb human HO-1 promoter and observed significant heme- and cadmium-mediated induction of the reporter gene, suggesting the presence of an internal enhancer. Enhancer function was orientation independent and required a region between -3.5 and -4.5 kb of the human HO-1 promoter. Our studies identified a novel enhancer internal to the human HO-1 gene that, in conjunction with the HO-1 promoter, recapitulates heme- and cadmium-mediated induction of the endogenous HO-1 gene. Elucidation of the molecular regulation of the human HO-1 gene will allow for the development of therapeutic strategies to manipulate HO-1 gene expression in pathological states.
  • Keywords

  • Aorta, Cadmium, Cells, Cultured, Endothelium, Vascular, Enhancer Elements, Genetic, Enzyme Induction, Heme, Heme Oxygenase (Decyclizing), Heme Oxygenase-1, Human Growth Hormone, Humans, Kidney Tubules, Proximal, Membrane Proteins, Promoter Regions, Genetic, Transcription, Genetic
  • Digital Object Identifier (doi)

    Author List

  • Hill-Kapturczak N; Sikorski E; Voakes C; Garcia J; Nick HS; Agarwal A
  • Start Page

  • F515
  • End Page

  • F523
  • Volume

  • 285
  • Issue

  • 3