Analysen zum transformierenden Potenzial des E4orf3-Proteins von Adenovirus Serotyp 5
The transforming potential of human adenoviruses has been traditionally ascribed to the E1A and E1B transcription units encoded within early region 1 (E1). These gene products are sufficient to initiate complete cell transformation by virtue of their ability to interact with and manipulate the functions of several growth-regulatory proteins that control cell cycle progression and programmed cell death. Recently we and others have shown that two additional proteins of early region 4 (Ad5 E4orf6
... gion 4 (Ad5 E4orf6 and E4orf3) possess transforming and oncogenic potential. It appears that the 34-kDa gene product encoded within open reading frame 6 (E4orf6) contributes to oncogenic transformation by modulating the function and stability of the tumor suppressor protein p53. By contrast, the transforming activities of E4orf3 involve the reorganization of PML oncogenic domains (PODs) and possibly other still unknown cellular factors. Here we show that E4orf3, like E1A, interacts with the transcriptional coactivator p300 in vitro and in vivo. Binding of E4orf3 to p300 causes a dramatic relocalization of the cellular protein from a diffuse distribution into track-like structures. Also, similar to E1A, E4orf3 represses p300- mediated transactivation in transient reporter gene assays. The functional significance of the E4orf3/p300 interaction is further supported by the observation, that E4orf3 can complement a transformation-deficient E1A-mutant, lacking the p300 binding region CR1 in BRK focus-assays. These results demonstrate for the first time that adenovirus type 5 encodes for two different gene products (E1A and E4orf3) that can independently bind to p300. In addition our results suggest that the transforming potential of E4orf3 is related to its ability to modulate p300 functions.