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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 4, April, 2002 475-483

Cloning and Functional Analysis of the Mouse 5-Lipoxygenase Promoter

Eric S. Silverman, Louis Le, Rebecca M. Baron, Arlene Hallock, Josephine Hjoberg, Toshiki Shikanai, Karin Storm van's Gravesande, Philip E. Auron, and Weining Lu

Pulmonary and Critical Care Division and Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; Physiology Program, Department of Environmental Health, Harvard School of Public Health; and The New England Baptist Bone and Joint Institute, Beth Israel Deaconess Medical Center; and Department of Medicine, Harvard Medical School, Boston, Massachusetts

5-Lipoxygenase (ALOX5), an enzyme essential for the formation of all leukotrienes, is highly regulated at multiple levels, including gene transcription. The human ALOX5 promoter sequence has been cloned and is well characterized. Several important cis-acting elements have been identified including a G+C-rich sequence ~ 145-179 base pairs (bp) upstream from the ATG start codon. This region contains consensus-binding sites for the transcription factor serum protein 1, a zinc-finger transcription factor (SP1) and early growth-response protein 1, a zinc-finger transcription factor (EGR-1) and is unique in that functionally significant polymorphisms alter these sequences. To further understand the significance of these polymorphisms and other regulatory sequences in the promoter we cloned ~ 2,000 bp of the mouse promoter sequence from a 129/SvJ BAC library for direct comparison with the human gene. Like the human promoter, the mouse Alox5 promoter lacks a TATA box and has multiple start sites. The first 292 bp immediately upstream of the translational start site function as a core promoter that is capable of mediating high basal transcription in RAW cells but not 3T3 cells. There are vast differences in the distribution of consensus cis elements between human and mouse genes; however, three areas of strong homology exist and they contain consensus-binding sites for the SP1, GATA, GGAGA, and ETS family of transcription factors. We show that Sp1/Sp3 is essential for constitutive promoter-reporter activity.

Abbreviations: 5-lipoxygenase, Alox5; adenosine triphosphate, ATP; base pairs, bp; early growth-response protein 1, EGR-1; electrophoretic mobility shift assay, EMSA; kilobase pairs, Kb; leukotriene, LT; an ETS transcription factor, PU.1/SPI-1; serum protein 1, SP1; wild-type genotype, WT.




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