Distinct Regulation of p53 and p73 Activity by Adenovirus E1A, E1B, and E4orf6 Proteins

Abstract

Multiple adenovirus (Ad) early proteins have been shown to inhibit transcription activation by p53 and thereby to alter its normal biological functioning. Since these Ad proteins affect the activity of p53 via different mechanisms, we examined whether this inhibition is target gene specific. In addition, we analyzed whether the same Ad early proteins have a comparable effect on transcription activation by the recently identified p53 homologue p73. Our results show that the large E1B proteins very efficiently inhibited the activity of p53 on the Bax, p21Waf1 , cyclin G, and MDM2 reporter constructs but had no effect on the activation of the same reporter constructs by p73, with the exception of some inhibition of the Bax promoter by Ad12 E1B. The repressive effect of the E1A proteins on p53 activity is less than that seen with the large E1B proteins, but the E1A proteins inhibit the activity of both p53 and p73. We could not detect significant inhibition of p53 functions by E4orf6, but a clear repression of the transcription activation by p73 by this Ad early protein was observed. In addition, we found that stable expression of the Ad5 E1A and that of the E1B protein both caused increased p73 protein expression. The large E1B and the E4orf6 proteins together do not target the p73 protein for rapid degradation after adenoviral infection, as has previously been found for the p53 protein, probably because the large E1B protein does not interact with p73. Our results suggest that the p53 and p73 proteins are both inactivated after Ad infection and transformation but via distinct mechanisms.By regulating the expression of different target genes, p53 can affect important cellular processes like cell cycle progression and apoptosis. Multiple adenovirus early (Ad E) proteins have been shown to inhibit the transcription activation potential of p53 via different mechanisms and thereby to impair its normal biological functioning. The first Ad E protein identified as inhibiting p53 activity was the large E1B protein (38). Yew and colleagues have shown that in the presence of the large E1B protein p53 can still bind to its consensus sequence but that the transcription-repressive regions present in the large E1B protein inhibit the transcription activation potential of p53 (39). In addition, we and others have shown that the E1A proteins also can inhibit transcription activation by p53 (27,30). The E1A proteins can directly interact with the p300 protein, which not only serves as a cofactor for p53 transactivation but also activates its sequence-specific DNA binding by acetylation of the C terminus of p53 (6, 7, 12). The third Ad E protein which has been reported to inhibit transcription activation by p53 is the E4orf6 protein. Dobner and coworkers reported that E4orf6 inhibits the activity of p53 by a direct interaction with the C terminus of p53 which inhibits binding of TAF32 to the transcription activation domain of p53 (2). It is currently unclear why Ads produce such a number of different proteins all causing repression ...

Structure, function and regulation of p63 and p73

“…31 The Adenovirus E1B 55 K protein also binds to p53 but does not interact with p73 (a or b). 29,32,33 As expected, the E1B 55 K protein inhibited the transactivating function of p53 but not p73. Therefore, three viral oncoproteins known to inhibit p53, i.e., HPV-16 E6, SV40 T-Antigen and E1B55 K, do not inhibit the function of p73.…”

Adenoviral E1B55K oncoprotein sequesters candidate leukemia suppressor sequence-specific single-stranded DNA-binding protein 2 into aggresomes

“…Simultaneously, E1B55K inactivates the p53 pathway by inhibiting p53-mediated transcription, thereby preventing growth arrest and apoptosis (Yew and Berk, 1992;Yew et al, 1994;Teodoro and Branton, 1997;Martin and Berk, 1998). During adenovirus infection, E1B55K also associates with the viral E4orf6 protein and cellular proteins, forming an E3 ubiquitin ligase complex that induces proteasomal degradation of p53 (Querido et al, 1997(Querido et al, , 2001aSteegenga et al, 1998Steegenga et al, , 1999Cathomen and Weitzman, 2000;Wienzek et al, 2000;Harada et al, 2002). The E1B55K/E4orf6 complex also degrades cellular DNA repair proteins to prevent a DNA damage response (Stracker et al, 2002;Carson et al, 2003) and is required for RNA transport and late protein synthesis during infection (Dobner and Kzhyshkowska, 2001;Flint and Gonzalez, 2003).…”

Amphiphysin IIb-1, a novel splicing variant of amphiphysin II, regulates p73β function through protein-protein interactions

“…Moreover, steady-state levels of p73 are not altered by interactions with mdm2, which induces proteasome-mediated degradation of p53 (Haupt et al, 1997;Zeng et al, 1999;Dobbelstein et al, 1999). Equally, multiple adenoviral proteins that bind and inhibit the activity of p53 do not interact with p73 (Martin et al, 1998;Roth et al, 1998;Steegenga et al, 1999;Wienzek et al, 2000). These observations raise a possibility that distinct processes contribute to the biological activities of p73 and p53.…”