Affiliation:
1. Laboratory of Molecular and Developmental Biology, National Eye Institute, Bethesda, Maryland
Abstract
ABSTRACT
Here we examine the molecular basis for the known preferential expression of rabbit aldehyde dehydrogenase class 1 (ALDH1A1) in the cornea. The rabbit
Aldh1a1
promoter-firefly luciferase reporter transgene (−3519 to +43) was expressed preferentially in corneal cells in transfection tests and in transgenic mice, with an expression pattern resembling that of rabbit
Aldh1a1
. The 5′ flanking region of the rabbit
Aldh1a1
gene resembled that in the human gene (60.2%) more closely than that in the mouse (46%) or rat (51.5%) genes. We detected three xenobiotic response elements (XREs) and one E-box consensus sequence in the rabbit
Aldh1a1
upstream region; these elements are prevalent in other highly expressed corneal genes and can mediate stimulation by dioxin and repression by CoCl
2
, which simulates hypoxia. The rabbit
Aldh1a1
promoter was stimulated fourfold by dioxin in human hepatoma cells and repressed threefold by CoCl
2
treatment in rabbit corneal stromal and epithelial cells. Cotransfection, mutagenesis, and gel retardation experiments implicated the hypoxia-inducible factor 3α/aryl hydrocarbon nuclear translocator heterodimer for
Aldh1a1
promoter activation via the XREs and stimulated by retinoic acid protein 13 for promoter repression via the E-box. These experiments suggest that XREs, E-boxes, and PAS domain/basic helix-loop-helix transcription factors (bHLH-PAS) contribute to preferential rabbit
Aldh1a1
promoter activity in the cornea, implicating hypoxia-related pathways.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
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