Elf-1 and PU.1 induce expression of gp91(phox) via a promoter element mutated in a subset of chronic granulomatous disease patients.
The cytochrome b heavy chain (gp91(phox)) is the redox center of the NADPH-oxidase and is highly expressed in mature myeloid cells. Point mutations at -57, -55, -53, and -52 bp of the gp91(phox) promoter have been detected in patients with chronic granulomatous disease (CGD; Newburger et al, J Clin Invest 94:1205, 1994; and Suzuki et al, Proc Natl Acad Sci USA 95:6085, 1998). We report that Elf-1 and PU. 1, ets family members highly expressed in myeloid cells, bind to this promoter element. Either factor trans-activates the -102 to +12 bp gp91(phox) promoter when overexpressed in nonhematopoietic HeLa cells or the PLB985 myeloid cell line. However, no synergy of gp91(phox) promoter activation occurs when both Elf-1 and PU.1 are overexpressed. Introduction of the -57 bp or -55 bp CGD mutations into the gp91(phox) promoter significantly reduces the binding affinity of Elf-1 and PU.1 and also reduces the ability of these factors to trans-activate the promoter. These results indicate that Elf-1 and PU.1 contribute to directing the lineage-restricted expression of the gp91(phox) gene in phagocytes and that failure of these factors to effectively interact with this promoter results in CGD.
Voo
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Herman B Wells Center for Pediatric Research, Section of Pediatric Hematology/Oncology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Skalnik
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DG
D001483:Base Sequence; D001665:Binding Sites; D036383:Ephrin-A2; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006105:Granulomatous Disease, Chronic / Q000145:classification / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D020298:U937 Cells; D000099232:Proto-Oncogene Protein Spi-1
D036383:Ephrin-A2; D017261:Glycosylphosphatidylinositols; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C056558:CYBB protein, human