Role of protein-protein interactions in the antiapoptotic function of EWS-Fli-1.
In the majority of Ewing's family tumors, chromosomal translocation t(11;22) leads to aberrant fusion of RNA-binding protein EWS with DNA-binding ETS transcriptional factor Fli-1. EWS-Fli-1 has altered the transcriptional activity and modulating its downstream target genes through this transcriptional activity is thought to be responsible for this tumor. We have previously shown that both EWS-Fli-1 and Fli-1 have antiapoptotic activity against several apoptotic inducers. Here, we show that the transcriptional activity of EWS-Fli-1 and Fli-1 is not essential for its antiapoptotic activity. We also demonstrate that EWS-Fli-1 and Fli-1 interact with CBP through its amino-terminal region and inhibit the CBP-dependent transcriptional activity of RXR. This activity appears to be independent of DNA-binding activity of EWS-Fli-1. Introduction of the dominant-negative form of CBP into Ewing's sarcoma cells sensitizes these cells against genotoxic or retinoic-acid induced apoptosis. These results suggest that the ability of EWS-Fli-1/Fli-1 to target transcriptional cofactor(s) and modulate apoptotic pathways may be responsible for its antiapoptotic and tumorigenic activities.
Drexel University, Broad and Vine, Philadelphia, PA 19102, USA.
Ramugounder
R
Ramakrishnan
Yasuo
Y
Fujimura
Jian Ping
JP
Zou
Fang
F
Liu
Leo
L
Lee
Veena N
VN
Rao
E Shyam P
ES
Reddy
D000199:Actins / Q000235:genetics; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D001859:Bone Neoplasms / Q000235:genetics*; D002470:Cell Survival / Q000502:physiology*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D017931:DNA Primers; D018260:Gelsolin / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D008840:Microfilament Proteins; D016133:Polymerase Chain Reaction / Q000379:methods; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012512:Sarcoma, Ewing / Q000235:genetics*; D015534:Trans-Activators; D014158:Transcription, Genetic; D014162:Transfection; D014178:Translocation, Genetic
D000199:Actins; D017931:DNA Primers; C098179:FLII protein, human; D018260:Gelsolin; D008840:Microfilament Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators