Promoters containing ATF-binding sites are de-regulated in cells that express the EWS/ATF1 oncogene.
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.
Brown
A D
AD
Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Hertfordshire, UK.
Lopez-Terrada
D
D
Denny
C
C
Lee
K A
KA
D051697:Activating Transcription Factor 1; D001483:Base Sequence; D002869:Chromosome Aberrations / Q000235:genetics; D025063:Chromosome Disorders; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D066298:In Vitro Techniques; D008545:Melanoma / Q000235:genetics*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000235:genetics*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012261:Ribonucleoproteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014178:Translocation, Genetic
D051697:Activating Transcription Factor 1; D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012261:Ribonucleoproteins; D014157:Transcription Factors