Recruitment of CREB-binding protein by PU.1, IFN-regulatory factor-1, and the IFN consensus sequence-binding protein is necessary for IFN-gamma-induced p67phox and gp91phox expression.
Activation of the phagocyte respiratory burst oxidase requires interaction between the oxidase components p47phox, p67phox, p22phox, and gp91phox. IFN-gamma induces transcription of the genes encoding p67phox (the NCF2 gene) and gp91phox (the CYBB gene) during monocyte differentiation, and also in mature monocytes. In these studies, we identify an NCF2 cis element, necessary for IFN-gamma-induced p67phox expression, and determine that this element is activated by cooperation between the transcription factors PU.1, IFN regulatory factor 1 (IRF1), and the IFN consensus-binding protein (ICSBP). Previously, we identified a CYBB cis element, necessary for IFN-gamma-induced gp91phox expression, and also activated by this transcription factor combination. In these investigations, we determine that recruitment of a coactivator protein, CBP (the CREBbinding protein), to the CYBB or NCF2 promoter is the molecular mechanism of transcriptional activation by PU.1, IRF1, and ICSBP. Also, we determine that the multiprotein interaction of CBP with PU. 1, IRF1, and ICSBP requires either the CYBB- or NCF2--binding site. Because IFN-gamma induces simultaneous expression of p67phox and gp91phox, these investigations identify a molecular event that coordinates oxidase gene transcription during the inflammatory response. Also, these investigations identify CBP recruitment by cooperation between PU.1, IRF1, and ICSBP as a novel molecular mechanism for IFN-gamma-induced activation of myeloid genes that are involved in the system of host defense.
Eklund
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Lurleen B. Wallace Tumor Institute, Department of Hematology and Oncology and the Comprehensive Cancer Center, University of Alabama, Birmingham, and The Birmingham Veterans Administration Hospital, Birmingham, AL 35294, USA. elizabeth.eklund@ccc.uab.edu
Kakar
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D001483:Base Sequence; D001665:Binding Sites; D001853:Bone Marrow / Q000276:immunology; D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000494:pharmacology*; D007438:Introns; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1
D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; C494257:IRF1 protein, human; C079789:neutrophil cytosol factor 67K; C056558:CYBB protein, human; C494363:CREBBP protein, human