Title

ESE-1 is a novel transcriptional mediator of angiopoietin-1 expression in the setting of inflammation

UMMS Affiliation

Department of Medicine, Division of Rheumatology

Date

3-26-2004

Document Type

Article

Medical Subject Headings

Angiopoietin-1; Animals; Arthritis, Rheumatoid; Binding Sites; Blotting, Western; Cell Line; Cell Line, Tumor; Chemotaxis; Cytokines; DNA; DNA Mutational Analysis; DNA, Complementary; DNA-Binding Proteins; Fibroblasts; *Gene Expression Regulation; Genes, Reporter; Genetic Vectors; Humans; Immunohistochemistry; Inflammation; Luciferases; Mice; Mutagenesis, Site-Directed; Mutation; NIH 3T3 Cells; Oligonucleotide Array Sequence Analysis; Oligonucleotides; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ets; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factor AP-1; Transcription Factors; *Transcription, Genetic; Transcriptional Activation; Tumor Necrosis Factor-alpha; Up-Regulation

Disciplines

Biochemistry | Cellular and Molecular Physiology | Musculoskeletal Diseases | Rheumatology | Skin and Connective Tissue Diseases

Abstract

Angiogenesis is a critical component of the inflammatory response associated with a number of conditions. Angiopoietin-1 (Ang-1) is an angiogenic growth factor that promotes the chemotaxis of endothelial cells and facilitates the maturation of new blood vessels. Ang-1 expression is up-regulated in response to tumor necrosis factor-alpha (TNF-alpha). To begin to elucidate the underlying molecular mechanisms by which Ang-1 gene expression is regulated during inflammation, we isolated 3.2 kb of the Ang-1 promoter that contain regulatory elements sufficient to mediate induction of the promoter in response to TNF-alpha, interleukin-1beta, and endotoxin. Surprisingly, sequence analysis of this promoter failed to reveal binding sites for transcription factors that are frequently associated with mediating inflammatory responses, such as NF-kappaB, STAT, NFAT, or C/EBP. However, putative binding sites for ETS and AP-1 transcription factor family members were identified. Interestingly, among a panel of ETS factors tested in a transient transfection assay, only the ETS factor ESE-1 was capable of transactivating the Ang-1 promoter. ESE-1 binds to specific ETS sites within the Ang-1 promoter that are functionally important for transactivation by ESE-1. ESE-1 and Ang-1 are induced in synovial fibroblasts in response to inflammatory cytokines, with ESE-1 induction slightly preceding that of Ang-1. Mutation of a high-affinity ESE-1 binding site leads to a marked reduction in Ang-1 transactivation by ESE-1, inducibility by inflammatory cytokines, and DNA binding to the ESE-1 protein. Transcriptional profiling of cells transiently transfected with an ESE-1 expression vector demonstrates that the endogenous Ang-1 gene is directly inducible by ESE-1. Finally, Ang-1 and ESE-1 exhibit a similar and strong expression pattern in the synovium of patients with rheumatoid arthritis. Our results support a novel paradigm for the ETS factor ESE-1 as a transcriptional mediator of angiogenesis in the setting of inflammation.

Rights and Permissions

Citation: J Biol Chem. 2004 Mar 26;279(13):12794-803. Epub 2004 Jan 8. Link to article on publisher's site

Comments

At the time of publication, Ellen Gravallese was not yet affiliated with the University of Massachusetts Medical School

Related Resources

Link to Article in PubMed

PubMed ID

14715662