E1A physically interacts with RUNX3 and inhibits its transactivation activity.
The adenoviral gene, termed early region 1A (E1A), is crucial for transformation and has been used very effectively as a tool to determine the molecular mechanisms that underlie the basis of cellular transformation. pRb, p107, p130, p300/CBP, p400, TRRAP, and CtBP were identified to be E1A-binding proteins and their roles in cellular transformation have been established. Although the major function of E1A is considered to be the regulation of gene expression that is critical for differentiation and cell cycle exit, one of the most significant questions relating to E1A transformation is how E1A mediates this regulation. RUNX3 is a transcription factor that was first described as a gastric cancer tumor suppressor but is now known to be involved in many different cancers. Exogenous expression of RUNX3 strongly inhibits the growth of cells. Here, we show that the adenovirus oncoprotein E1A interacts with RUNX3 in vitro and in vivo. RUNX3 interacts with the N-terminus (amino acids 2-29) of E1A, which is known to interact with p300/CBP, p400, and TRRAP. E1A interacts directly with the Runt domain of RUNX3 but does not interfere with CBFbeta-RUNX3 interactions. In addition, E1A inhibits the transactivation activity of RUNX3 on the p21(WAF1/CIP1) promoter. Consistent with these observations, the growth inhibition induced by RUNX3 is reduced by E1A. These results demonstrate that E1A specifically binds to RUNX3 and inactivates its transactivation activity. We propose that one of the mechanisms for the oncogenic activity of E1A is the inhibition of RUNX3, similar to that of RB and p300/CBP.
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Eun-Jeong
EJ
Cha
Byung-Chul
BC
Oh
Hee-Jun
HJ
Wee
Xin-Zi
XZ
Chi
Yun-Mi
YM
Goh
Kyeong-Sook
KS
Lee
Yoshiaki
Y
Ito
Suk-Chul
SC
Bae
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D023081:CCAAT-Binding Factor / Q000378:metabolism; D002460:Cell Line; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D015533:Transcriptional Activation / Q000235:genetics*
D017500:Adenovirus E1A Proteins; D023081:CCAAT-Binding Factor; D050677:Core Binding Factor Alpha 3 Subunit