All ETDs from UAB

Advisory Committee Chair

Anupam Agarwal

Advisory Committee Members

Bruce Freeman

Thomas Ryan

Paul Sanders

Bradley Yoder

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


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.



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