Distinct regulation of p53 and p73 activity by adenovirus E1A, E1B, and E4orf6 proteins

Multiple adenovirus (Ad) early proteins have been shown to inhibit transcri ption activation by p53 and thereby to alter its normal biological function ing. Since these Ad proteins affect the activity of p53 via different mecha nisms, we examined whether this inhibition is target gene specific. In addi tion, we analyzed whether the same Ad early proteins have a comparable effe ct on transcription activation by the recently identified p53 homologue p73 . Our results show that the large E1B proteins very efficiently inhibited t he activity of p53 on the Bax, p21(Waf1), cyclin G, and MDM2 reporter const ructs but had no effect on the activation of the same reporter constructs b y p73, with the exception of some inhibition of the Bax promoter by Ad12 E1 B. The repressive effect of the E1A proteins on p53 activity is less than t hat seen with the large E1B proteins, but the E1A proteins inhibit the acti vity of both p53 and p73. We could not detect significant inhibition of p53 functions by E4orf6, but a clear repression of the transcription activatio n 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 in creased p73 protein expression. The large E1B and the E4orf6 proteins toget her do not target the p73 protein for rapid degradation after adenoviral in fection, 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 trans formation but via distinct mechanisms.