TY - JOUR
T1 - Elf-1 and PU.1 induce expression of gp91(phox) via a promoter element mutated in a subset of chronic granulomatous disease patients
AU - Voo, Kui Shin
AU - Skalnik, David G.
PY - 1999/5/15
Y1 - 1999/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0001324766&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0001324766&partnerID=8YFLogxK
U2 - 10.1182/blood.v93.10.3512.410k19_3512_3520
DO - 10.1182/blood.v93.10.3512.410k19_3512_3520
M3 - Article
C2 - 10233904
AN - SCOPUS:0001324766
SN - 0006-4971
VL - 93
SP - 3512
EP - 3520
JO - Blood
JF - Blood
IS - 10
ER -