Advisor(s)
Anupam Agarwal
Committee Member(s)
Bruce Freeman
Thomas Ryan
Paul Sanders
Bradley Yoder
Document Type
Dissertation
Date of Award
2007
Abstract
The heme oxygenase-1 (HO-1) gene encodes a microsomal enzyme that catalyzes the conversion of heme to carbon monoxide, Iron, and biliverdin. HO-1 transcription is induced upon a plethora of cellular stresses including heme, heavy metal exposure, hy-poxia, oxidative stress and many others. The goal of this work was to explore the molecu-lar regulation of HO-1 transcription. Four DNase 1 hypersensitive sites are detected within the HO-1 promoter extending from ~-40bp to ~-9.2kb relative to the transcription start site. Dimethylsulfate (DMS) in vivo footprinting is shown for two regulatory re-gions and reveals nine protected guanines in all. Mutational analyses indicates that three regions are responsible for HO-1 minimal promoter activity under the influence of the potent inducers hemin and cadmium. The upstream stimulatory factors USF1 and USF2 bind to a proximal promoter region and ablation of their endogenous activities reduces HO-1 induction. Jun transcription factors are also shown to associate with the HO-1 promoter in vivo. JunB overexpression was sufficient to induce HO-1 in unstimulated cells while JunD overexpression results in severely inhibited HO-1 induction under hemin stimulation. Loss of JunB in mouse embryonic fibroblasts (MEF) cells resulted in greatly reduced HO-1 induction while loss of JunD increased HO-1 induction upon hemin stimulation. These studies provide the first in depth in vivo analysis of HO-1 mo-lecular regulation and provide a link between Jun transcription factors and HO-1 induc-tion.
ProQuest Publication Number
ISBN
978-0-549-46842-4
Recommended Citation
Hock, Thomas D., "Regulation Of The Human Heme Oxygenase-1 Gene" (2007). All ETDs from UAB. 3716.
https://digitalcommons.library.uab.edu/etd-collection/3716
