Identification of ETS-1 target genes in human fibroblasts

Abstract

Abstract. The transcription factor Ets-1 plays several distinct critical roles in tumour development and progression by acting both in neoplastic cells and in the tumour stroma. Increased expression of Ets-1 in tumours is often associated with a worse prognosis. Stromal fibroblasts attribute an important part to the behaviour of malignant tumours. In this study we investigated the role of Ets-1 in the tumour stroma. It is well known that ets-1 expression in fibroblasts -one of the main components of the tumour stroma -can be induced by basic fibroblast growth factor (bFGF). We applied suppression subtractive hybridization (SSH) to identify genes that are differentially expressed between bFGF stimulated wild-type fibroblasts and fibroblasts with reduced Ets-1 expression. We selected clones up-or down-regulated in bFGF stimulated wild-type fibroblasts using SSH and functionally characterized them by reference to public databases using NCBI BLAST tools. Expression levels of genes corresponding to subtracted clones were analyzed using RT-PCR. Known genes were associated with diverse functions; novel Ets-1 regulated genes identified by SSH not only encoded components involved in matrix degradation (as cathepsin and PAI-2) but also constituents of the extracellular matrix (ECM) including α-2-Type I collagen, TGF-β induced protein, lumican and decorin. Our findings identify several potential novel target genes of Ets-1, and they provide potentially important insights into the role of Ets-1 in stromal fibroblasts for both remodelling and different functionalities of the ECM.

Getting Out of a Sticky Situation: Targeting the Myofibroblast in Scleroderma

“…The transcription factors fli-1 and ets-1 occupy the same sites on promoters; TGFβ stimulation results in replacement of fli-1 on the CCN2 promoter with ets-1 [30]. Indeed, ets-1 seems to generally regulate the expression of profibrotic genes in fibroblasts [31-33]. Thus, targeting the syndecan4/ERK/ets-1 pathway may be a good target for anti-fibrotic therapy in SSc [33].…”

Transcriptional regulation of Hepatic Stellate Cell activation in NASH

“…While it is recognized that activation and transdifferentiation of quiescent HSCs to myofibroblasts involves profound changes in gene expression, little is known about the transcriptional effectors of the above signals. The best described transcriptional regulators of HSC transdifferentiation are the transcription factors (TFs) SMAD3 and STAT3 conveying growth factor and cytokine signals to the genome 18,19 , but other transcriptional regulators, including YAP1 20 , GLI2 21 , AP-1 22 , SOX9 23 , and ETS family members 24,25 , may also be involved by activating key fibrogenic genes.…”

Cellular Repressor of E1A-Stimulated Genes Is a Critical Determinant of Vascular Remodeling in Response to Angiotensin II

“…28 In most cases, Ets1 positively regulates the expression of its target genes. However, Ets1 also functions as repressor of its target genes, [28][29][30] including interleukin-10, cyclin D3, retinoblastoma-associated factor 600, AXL receptor tyrosine kinase, MET tyrosine kinase, β-2-adrenergic receptor, stromal cell-derived factor receptor 1, ATP5G3, 5-tubulin, serine-threonine-kinase 6, and anilin/actin-binding protein. In addition, Ets1 can also suppress gene expression through interacting with repressive factors like EAP1/Daxx, HDAC1, mSin3a, and DNA methyltransferase 3a and 3b.…”