title: Acetylation impacts Fli-1-driven regulation of granulocyte colony stimulating factor.
abstract: Fli-1 has emerged as a critical regulator of inflammatory mediators, including MCP-1, CCL5, and IL-6. The cytokine, granulocyte colony stimulating factor (G-CSF) regulates neutrophil precursor maturation and survival, and activates mature neutrophils. Previously, a significant decrease in neutrophil infiltration into the kidneys of Fli-1+/-lupus-prone mice was observed. In this study, a significant decrease in G-CSF protein expression was detected in stimulated murine and human endothelial cells when expression of Fli-1 was inhibited. The murine G-CSF promoter contains numerous putative Fli-1 binding sites and several regions within the proximal promoter are significantly enriched for Fli-1 binding. Transient transfection assays indicate that Fli-1 drives transcription from the G-CSF promoter and mutation of the Fli-1 DNA binding domain resulted in a 94% loss of transcriptional activation. Mutation of a known acetylation site, led to a significant increase in G-CSF promoter activation. The histone acetyltransferases p300/CBP and p300/CBP associated factor (PCAF) significantly decrease Fli-1 specific activation of the G-CSF promoter. Thus, acetylation appears to be an important mechanism behind Fli-1 driven activation of the G-CSF promoter. These results further support the theory that Fli-1 plays a major role in the regulation of several inflammatory mediators, ultimately affecting inflammatory disease pathogenesis.
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Mara L
authors.initials: ML
authors.lastname: Lennard Richard
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Brandon
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, USA.|Jinan Central Hospital, Shandong University, Jinan, Shangdong, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Lou
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Shuzo
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Tomika
authors.initials: T
authors.lastname: Caldwell
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Tamara K
authors.initials: TK
authors.lastname: Nowling
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, USA.|Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Gilkeson
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, USA. zhangjo@musc.edu.|Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA. zhangjo@musc.edu.
authors.forename: Xian K
authors.initials: XK
authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D000818:Animals; D042783:Endothelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D016179:Granulocyte Colony-Stimulating Factor; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Cytokines; Fli-1; G-CSF; Gene regulation; Inflammation; Transcriptional factors