Nucleic Acids Research, Vol 24, Issue 6 1052-1058, Copyright © 1996 by Oxford University Press
L Magnaghi-Jaulin, H Masutani, P Robin, M Lipinski and A Harel-Bellan
EWS-FLI-1 is a chimeric protein produced in most Ewing's sarcomas. It
results from the fusion of the N-terminal-encoding region of the EWS gene
to the C-terminal DNA-binding domain (the ETS domain) encoded by the FLI-1
ets family gene. Both EWS-FLI-1 and FLI-1 proteins function as
transcription factors that bind specifically to ets sequences (the ets
boxes) present in promoter elements. EWS- FLI-1 is a powerful transforming
protein, whereas FLI-1 is not. In a search for potential DNA binding sites
for these two proteins, we have tested their ability to recognize the serum
responsive element (SRE) in the c-fos promoter. This cis element contains
an ets box which can be occupied by members of the ETS protein family which
do not bind DNA autonomously but form a ternary complex with a second
protein, p67SRF (serum responsive factor). We demonstrate here that
EWS-FLI-1, but not FLI-1, is able to form a ternary complex on the c-fos
SRE. Using a GST pull-down assay, we show that both FLI-1 and EWS-FLI-1
interact in vitro with SRF in the absence of DNA. In electromobility shift
assays, EWS-FLI-1 binding to the SRE is detectable in the absence of SRF
whereas the binding of FLI- 1 is not, suggesting that the interaction with
DNA is the step which limits ternary complex formation by FLI-1. Deletion
of the N-terminal portion of FLI-1 resulted in a protein which behaved as
EWS-FLI-1, suggesting the existence of an N- terminal inhibitory domain in
the normal protein. Taken together, our data indicate that there are
intrinsic differences in the binding of EWS-FLI-1 and FLI-1 proteins to
distinct ets sequences.
ARTICLES
SRE elements are binding sites for the fusion protein EWS-FLI-1
Laboratoire de Biologie des Tumeurs Humaines, CNRS URA 1156, Villejuif, France.
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