Cooperative interaction of EWS with CREB-binding protein selectively activates hepatocyte nuclear factor 4-mediated transcription.
The EWS gene when fused to transcription factors such as the ETS family ATF-1, Wilms' tumor-1, and nuclear orphan receptors upon chromosomal translocation is thought to contribute the development of Ewing sarcoma and several malignant tumors. Although EWS is predicted to be an RNA-binding protein, an inherent EWS nuclear function has not yet been elucidated. In this study, we found that EWS associates with a transcriptional co-activator CREB-binding protein (CBP) and the hypophosphorylated RNA polymerase II, which are included preferentially in the transcription preinitiation complex. These interactions suggest the potential involvement of EWS in gene transcription, leading to the hypothesis that EWS may function as a co-activator of CBP-dependent transcription factors. Based on this hypothesis, we investigated the effect of EWS on the activation of nuclear receptors that are activated by CBP. Of nuclear receptors examined, hepatocyte nuclear factor 4-dependent transcription was selectively enhanced by EWS but not by an EWS mutant defective for CBP binding. These results suggest that EWS as a co-activator requires CBP for hepatocyte nuclear factor 4-mediated transcriptional activation.
Araya
Natsumi
N
Center for Tsukuba Advanced Research Alliance, Aspect of Functional Genomic Biology, Tsukuba, Ibaraki 305-8577, Japan.
Hirota
Keiko
K
Shimamoto
Yoko
Y
Miyagishi
Makoto
M
Yoshida
Eisaku
E
Ishida
Junji
J
Kaneko
Setsuko
S
Kaneko
Michio
M
Nakajima
Toshihiro
T
Fukamizu
Akiyoshi
A
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050882:CREB-Binding Protein; D002460:Cell Line; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics*; D034802:RNA-Binding Protein EWS / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D034802:RNA-Binding Protein EWS; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; C494363:CREBBP protein, human