Blockage by Adenovirus E4orf6 of Transcriptional Activation by the p53 Tumor Suppressor

Abstract

The adenovirus E4orf6 protein is shown here to interact with the cellular tumor suppressor protein p53 and to block p53-mediated transcriptional activation. The adenovirus protein inhibited the ability of p53 to bind to human TAFII31, a component of transcription factor IID (TFIID). Earlier work demonstrated that the interaction of p53 with TAFII31 involves a sequence near the NH2-terminus of p53, whereas the E4orf6-p53 interaction occurs within amino acids 318 to 360 of p53. Thus, the E4orf6 protein interacts at a site on p53 distinct from the domain that binds to TAFII31 but nevertheless inhibits the p53-TAFII31 interaction.

The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53

“…In addition, it has been demonstrated that p53-dependent growth suppression requires both the amino-and carboxy-terminal regions of p53 (Pietenpol et al, 1994). Because, both E1B-55 kDa and E4orf6 inhibit p53-activated transcription (Yew and Berk, 1992;Dobner et al, 1996), it is possible that they cooperate to block growth arrest induced by the residual low levels of p53. Furthermore, because E1B-55 kDa and E4orf6 bind to di erent domains on p53 (Lin et al, 1994;Dobner et al, 1996), it is also possible that both proteins bind to p53 simultaneously to antagonize this activity; although at present there is no direct evidence that such a trimeric complex exists.…”

“…Because, both E1B-55 kDa and E4orf6 inhibit p53-activated transcription (Yew and Berk, 1992;Dobner et al, 1996), it is possible that they cooperate to block growth arrest induced by the residual low levels of p53. Furthermore, because E1B-55 kDa and E4orf6 bind to di erent domains on p53 (Lin et al, 1994;Dobner et al, 1996), it is also possible that both proteins bind to p53 simultaneously to antagonize this activity; although at present there is no direct evidence that such a trimeric complex exists. In summary, our results indicate that E4orf6 enhances the intrinsic ability of E1-transformed rat cells to grow in a neoplastic state by di erent but synergistical mechanisms that completely inactivate p53 tumor suppressor functions.…”

“…E4orf6 also cooperates with E1A and E1B proteins to increase the number of cell transformants. The mechanism by which the E4orf6 protein enhances focus formation is not clear yet but is very likely related to the ability of E4orf6 to interact with and modulate functional properties of p53 (Dobner et al, 1996;Nevels et al, 1997). The E4orf6 protein can block p53-dependent apoptosis in transient transfection assays (Moore et al, 1996) and can inhibit p53-mediated suppression of E1A plus E1B-19 kDa-induced focus formation of primary rat cells .…”

“…The molecular basis of this process remains uncertain. Because E4orf6 interacts with both E1B-55 kDa (Sarnow et al, 1984) and p53 (Dobner et al, 1996;Moore et al, 1996;Nevels et al, 1997;Querido et al, 1997a), it is possible that multiple protein interactions between all three proteins exist in adenovirus-infected and transformed cells that modulate p53 functions and stability.…”

Adenovirus type 5 early region 1B 55-kDa oncoprotein can promote cell transformation by a mechanism independent from blocking p53-activated transcription

“…Mutant Ad5 E1B-55K plasmids ( Figure 1; Table 2 in Supplementary data) were generated from wt pE1B-55K (Endter et al, 2001) and pGal4E1B-55K (Dobner et al, 1996) by using the QuikChange Site-Directed Mutagenesis Kit (Stratagene Europe, Amsterdam, Netherlands), with complementary oligonucleotide pairs (Table 1 in Supplementary data). Plasmids pE1A (Endter et al, 2001), pC53-SN3 (Dobner et al, 1996), pEGFP (Clontech-Takara Europe, Saint-Germain-en-Laye, France) and the RGC-firefly luciferase reporter plasmids pGalTK-Luc (Nevels et al, 1997), pRELuc (Endter et al, 2001) and pCyclinG-Luc (Okamoto and Beach, 1994) have been described previously.…”