Promoters containing ATF-binding sites are de-regulated in cells that express the EWS/ATF1 oncogene.

ABSTRACT

Chromosomal translocations that fuse the N-terminal region of the Ewings sarcoma oncogene (EWS) to the C-terminal region (including the DNA-binding domain) of the cellular transcription factor ATF1 are associated with a tumour type termed malignant melanoma of soft parts (MMSP). It is envisioned that transformation by the EWS/ATF1 fusion protein results from aberrant transcriptional regulation of genes that are normally regulated by ATF1. To examine this hypothesis we have expressed exogenous EWS-ATF1 in JEG3 cells and tested its ability to activate several promoters that contain binding sites for ATF1. We show that EWS-ATF1 is a strong constitutive activator of some promoters tested but represses others. Significantly, the ability of particular promoters to be activated by EWS/ATF1 in JEG3 cells correlates with promoter activity in two MMSP-derived cell lines (SU-CCS-1 and DTC1). Our results therefore provide evidence that endogenous EWS/ATF1 can de-regulate transcription and that this capacity may contribute to transformation in MMSP.