EWS-ATF-1 chimeric protein in soft tissue clear cell sarcoma associates with CREB-binding protein and interferes with p53-mediated trans-activation function.
The recurrent t(12;22) (q13;q12) chromosomal translocation associated with soft tissue clear cell sarcoma results in a chimeric protein EWS-ATF-1 that acts as a constitutive transcriptional activator. The CBP/p300 transcriptional coactivator, which links various transcriptional factors to basal transcription apparatus, participates in transcriptional activation, growth and cell cycle control and differentiation. In this study, we show that EWS-ATF-1 associates constitutively with CBP both in vitro and in vivo. Both EWS and ATF-1 fusion domains are needed for this interaction. Here, we demonstrate that EWS-ATF-1 represses p53/CBP-mediated trans-activation function. Overexpression of CBP can counteract this repressive effect of EWS-ATF-1. Taken together, these findings suggest that one of the mechanisms by which EWS-ATF-1 may cause tumors is through targeting CBP/p300 resulting in the loss of function of p53. This novel mechanism may be responsible for the development of these and other related solid tumors.
Fujimura
Y
Y
Program of Cancer Genetics, Department of Biochemistry, School of Medicine, MCP Hahnemann University, Broad and Vine, Philadelphia, PA 19102, USA.
Siddique
H
H
Lee
L
L
Rao
V N
VN
Reddy
E S
ES
D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D016158:Genes, p53; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018227:Sarcoma, Clear Cell / Q000235:genetics* / Q000378:metabolism*; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
C111598:EWS-ATF1 fusion protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D005982:Glutathione Transferase