Molecular analysis of two closely related mouse aldehyde dehydrogenase genes: Identification of a role for Aldh1, but not Aldh-pb, in the biosynthesis of retinoic acid
Department of Biochemical Genetics, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.Biochemical Journal (Impact Factor: 4.4). 05/1999; 339 ( Pt 2)(2):387-95. DOI: 10.1042/0264-6021:3390387
Mammalian class I aldehyde dehydrogenase (ALDH1) has been implicated as a retinal dehydrogenase in the biosynthesis of retinoic acid, a modulator of gene expression and cell differentiation. As the first step towards studying the regulation of ALDH1 and its physiological role in the biosynthesis of retinoic acid, mouse ALDH1 cDNA and genomic clones have been characterized. During the cloning process, an additional closely related gene was also isolated and named Aldh-pb, owing to its high amino acid sequence identity (92%) with the rat phenobarbitol-inducible ALDH protein (ALDH-PB). Aldh1 spans about 45 kb in length, whereas Aldh-pb spans about 35 kb. Both genes are composed of 13 exons, and the positions of all the exon/intron boundaries are conserved with those of human ALDH1. The promoter regions of Aldh1 and Aldh-pb demonstrate high sequence similarity with those of human ALDH1 and rat ALDH-PB. Expression of Aldh1 and Aldh-pb is tissue-specific, with mRNAs for both genes being found in the liver, lung and testis, but not in the heart, spleen or muscle. Expression of Aldh-pb, but not Aldh1, was also detected at high levels in the kidney. Aldh1 and Aldh-pb encode proteins of 501 amino acids with 90% positional identity. To examine the relative roles of these two enzymes in retinoic acid synthesis in vivo, Xenopus embryos were injected with mRNAs encoding these enzymes to assay the effect on conversion of endogenous retinal into retinoic acid. Injection of ALDH1, but not ALDH-PB, mRNA stimulated retinoic acid synthesis in Xenopus embryos at the blastula stage. Thus our results indicate that Aldh1 can function in retinoic acid synthesis under physiological conditions, but that the closely related Aldh-pb does not share this property.
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- "The aldehyde dehydrogenase (ALDH) family members are cytosolic isoenzymes responsible for oxidizing intracellular aldehydes, including the oxidation of retinol (vitamin A) to retinoic acid, an important modulator of gene expression and cell differentiation. ALDH is highly expressed in hematopoietic stem cells[49,50]. In recent years ALDH1 has emerged as a prominent marker for CSCs in a number of solid tumors such as breast, colon, head and neck, prostate5152535455, and lung cancer. "
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- "Such information may assist interpretation of future research using transgenic models to study aldehyde toxicity in atherosclerosis and cardiovascular medicine. Although the human and mouse Aldh1a1 genes have been cloned and the promoter region characterized, little is known about the molecular mechanisms that regulate Aldh1a1 expression in mouse liver (Hsu et al., 1999; Elizondo et al., 2009). Previous studies identified a putative RA response element located at position Ϫ91/Ϫ75 adjacent to the CCAAT box of the hALDH1A1 gene, which is conserved in mouse Aldh1a1. "
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