The viral transactivator E1A regulates the mouse mammary tumor virus promoter in an isoform- and chromatin-specific manner

Abstract

Proteins encoded by the adenovirus E1A gene regulate both cellular and viral genes to mediate effects on cell cycle, differentiation, and cell growth control. We have identified the mouse mammary tumor virus (MMTV) promoter as a target of EIA action and investigated the role nucleoprotein structure plays in its response to E1A. Both 12 and 13 S forms target the MMTV promoter when it has a disorganized and accessible chromatin configuration. However, whereas the 13 S form is stimulatory, the 12 S form is repressive. When the MMTV promoter adopts an organized and repressed chromatin structure, it is targeted only by the 13 S form, which stimulates it. Although evidence indicates that EIA interacts with the SWI/SNF remodeling complex, E1A had no effect on chromatin remodeling at the MMTV promoter in organized chromatin. Analysis of EIA mutants showed that stimulation of the MMTV promoter is mediated solely through conserved region 3 and does not require interaction with Rb, p300/CBP associated factor, or CBP/p300. Imaging analysis showed that EIA colocalizes with MMTV sequences in vivo, suggesting that it functions directly at the promoter. These results indicate that EIA stimulates the MMTV promoter in a fashion independent of chromatin conformation and through a direct mechanism involving interaction with the basal transcription machinery.