Expression of GM-CSF Is Regulated by Fli-1 Transcription Factor, a Potential Drug Target
| Autor: | Xuan Wang, Mara Lennard Richard, Hongkuan Fan, Brittany Henry, Weiru Zhang, Gary S. Gilkeson, Steven Schutt, Xian K. Zhang, Pengfei Li, Xue-Zhong Yu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Sp1 Transcription Factor
T-Lymphocytes Immunology Regulator Article CCL5 Jurkat Cells Mice Transcription (biology) Animals Humans Immunology and Allergy Endothelium Molecular Targeted Therapy RNA Small Interfering Promoter Regions Genetic Transcription factor Sp1 transcription factor Proto-Oncogene Protein c-fli-1 Chemistry ETS transcription factor family fungi Granulocyte-Macrophage Colony-Stimulating Factor DNA-binding domain Cell biology Gene Expression Regulation NIH 3T3 Cells Camptothecin Topoisomerase I Inhibitors Chromatin immunoprecipitation |
| Zdroj: | J Immunol |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.2000664 |
| Popis: | Friend leukemia virus integration 1 (Fli-1) is an ETS transcription factor and a critical regulator of inflammatory mediators, including MCP-1, CCL5, IL-6, G-CSF, CXCL2, and caspase-1. GM-CSF is a regulator of granulocyte and macrophage lineage differentiation and a key player in the pathogenesis of inflammatory/autoimmune diseases. In this study, we demonstrated that Fli-1 regulates the expression of GM-CSF in both T cells and endothelial cells. The expression of GM-CSF was significantly reduced in T cells and endothelial cells when Fli-1 was reduced. We found that Fli-1 binds directly to the GM-CSF promoter using chromatin immunoprecipitation assay. Transient transfection assays indicated that Fli-1 drives transcription from the GM-CSF promoter in a dose-dependent manner, and mutation of the Fli-1 DNA binding domain resulted in a significant loss of transcriptional activation. Mutation of a known phosphorylation site within the Fli-1 protein led to a significant increase in GM-CSF promoter activation. Thus, direct binding to the promoter and phosphorylation are two important mechanisms behind Fli-1–driven activation of the GM-CSF promoter. In addition, Fli-1 regulates GM-CSF expression in an additive manner with another transcription factor Sp1. Finally, we demonstrated that a low dose of a chemotherapeutic drug, camptothecin, inhibited expression of Fli-1 and reduced GM-CSF production in human T cells. These results demonstrate novel mechanisms for regulating the expression of GM-CSF and suggest that Fli-1 is a critical druggable regulator of inflammation and immunity. |
| Databáze: | OpenAIRE |
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