L. Feng et Kaw. Lee, A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene, ONCOGENE, 20(31), 2001, pp. 4161-4168
Chromosomal fusion of the N-terminal region of the Ewings Sarcoma Oncogene
(EWS-activation-domain, EAD) to the DNA-binding domains of a variety of cel
lular transcription factors produce oncogenic proteins (EWS-fusion proteins
(EFPs)) that cause distinct malignancies. In EFPs, the EAD acts as a poten
t transcriptional activation domain and this ability is repressed in the co
ntext of normal, non-tumorigenic, EWS, Trans-activation by the EAD is there
fore a specific characteristic of EFPs and it is thought that EFPs induce t
umorigenesis via improper transcriptional activation of cellular genes. Fun
ctional elements required for transcriptional activation are dispersed thro
ughout the EAD, as are thirty-one copies of a Degenerate Hexapeptide Repeat
(DHR, consensus SYCQQS), This suggests that the EAD contains a highly reit
erated functional element related to DHRs. Here we show that in the context
of EWS/ATF1, the EFP that causes malignant melanoma of soft parts, trans-c
ooperation by small regions of the EAD (similar to 30 residues) results in
potent transcriptional activation dependent on the conserved tyrosine resid
ues present in DHRs, These findings provide the first evidence for a role o
f DHRs in EAD-mediated trans-activation and demonstrate that the EAD repres
ents a novel tyrosine-dependent transcriptional activation domain.