Repression of the gene encoding the TGF-β type II receptor is a major target of the EWS-FLI1 oncoprotein

Abstract

Chromosomal translocations resulting in the expression of chimaeric transcription factors are frequently observed in tumour cells, and have been suggested to be a common mechanism in human carcinogenesis. Ewing sarcoma and related peripheral primitive neuroectodermal tumours share recurrent translocations that fuse the gene EWSR1 (formerly EWS) from 22q-12 to FLI1 and genes encoding other ETS transcription factors (which bind DNA through the conserved ETS domain). It has been shown that transduction of the gene EWSR1-FLI1 (encoding EWS-FLI1 protein) can transform NIH3T3 cells, and that mutants containing a deletion in either the EWS domain or the DNA-binding domain in FLI1 lose this ability. This indicates that the EWS-FLI1 fusion protein may act as an aberrant transcription factor, but the exact mechanism of oncogenesis remains unknown. Because ETS transcription factors regulate expression of TGFBR2 (encoding the TGF-beta type II receptor, TGF-beta RII; Refs 9,14), a putative tumour suppressor gene, we hypothesized that TGFBR2 may be a target of the EWS-FLI1 fusion protein. We show here that Ewing sarcoma [corrected] (ES) cell lines with the EWSR1-FLI1 fusion have reduced TGF-beta sensitivity, and that fusion-positive ES cells and primary tumours both express low or undetectable levels of TGFBR2 mRNA and protein product. Co-transfection of FLI1 and the TGFBR2 promoter induces promoter activity, whereas EWSR1-FLI1 leads to suppression of TGFBR2 promoter activity and FLI1-induced promoter activity. Introduction of EWSR1-FLI1 into cells lacking the EWSR1-FLI1 fusion suppresses TGF-beta RII expression, whereas antisense to EWSR1-FLI1 in ES cell lines positive for this gene fusion restores TGF-beta RII expression. Furthermore, introduction of normal TGF-beta RII into ES cell lines restores TGF-beta sensitivity and blocks tumorigenicity. Our results implicate TGF-beta RII as a direct target of EWS-FLI1.

BCL2 Translocation Defines a Unique Tumor Subset within the Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

“…18 The precise functional alterations in the apoptotic pathway are difficult to predict from the gene expression data and it is possible that the apoptotic pathway is dominated by BCL2 overexpression in the vast majority of t(14;18)-positive cases. In addition to these genes, there is also overexpression of a heterogeneous group of transcription factors including FLI1 that regulates expression of the TGF-␤ type II receptor, 19 HOX11 that belongs to a family of DNA-binding transactivators, 20 and BAP135. BAP135 exists as a complex with Bruton Tyrosine Kinase (BTK) before B-cell antigen receptor engagement and is transiently tyrosinephosphorylated in response to B-cell receptor cross-linking.…”

Smad3 regulates E-cadherin via miRNA-200 pathway

“…Alterations or mutations in TGF-b-signaling molecules have been strongly associated with various types of human tumors, including gastric, colon, breast and prostate cancers (Park et al, 1994;Hahm et al, 1999;Kim et al, 2006). Defects in TGF-b receptor II have been linked with the resistance of tumor cells to the growth-inhibitory effects of TGF-b Parsons et al, 1995).…”

A link between basic fibroblast growth factor (bFGF) and EWS/FLI-1 in Ewing's sarcoma cells

“…The fusion protein has been found to be important for cell growth and tumor transformation (Tanaka et al, 1997;Toretsky et al, 1997). Recently, Hahm et al (1999) provided evidence that transformation growth factor-b type II receptor gene is a target for EWS/FLI-1. However, on the whole little is known about the target genes and how the expression of EWS/FLI-1 is regulated.…”