Repression of the c-Jun trans-activation function by the adenovirus type 12 E1a 52R protein correlates with the inhibition of phosphorylation of the c-Jun activation domain

Abstract

The early region 1A 52R polypeptide, a protein expressed exclusively by the in vivo oncogenic adenovirus subtype 12, represses the trans-activating function of the cellular transcription factor complex AP-1 consisting of c- Jun-c-Jun homodimers. In this report we demonstrate that the repression in vivo correlates with a direct physical interaction of the adenovirus protein with c-Jun in vitro. Interestingly, the 52R protein binds to the bZIP domain of c-Jun essential for dimerization and DNA binding but not to the c-Jun activation domain. This interaction does not prevent the promoter binding of c-Jun/AP-1. Moreover, the physical association between c-Jun and the TATA box-binding protein TBP is not disturbed by the 52R polypeptide. In fact, we show evidence that down-regulation of c-Jun activity by the adenoviral protein is due to the inhibition of phosphorylation of the c-Jun trans- activation domain. In vivo phosphorylation of the c-Jun activation domain is necessary for the interaction of c-Jun with specific cofactors such as CBP and therefore a prerequisite for the activation of target genes. Due to these results we propose a model in which the 52R protein represses the trans- activating function of c-Jun by preventing its phosphorylation through a specific kinase necessary for the activation of the cellular transcription factor.