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Journal of Virology, January 2001, p. 699-709, Vol. 75, No. 2
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.2.699-709.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification of Three Functions of the Adenovirus E4orf6 Protein That Mediate p53 Degradation by the E4orf6-E1B55K Complex

Emmanuelle Querido,1,dagger Megan R. Morisson,1 Huan Chu-Pham-Dang,1 Sarah W.-L. Thirlwell,1 Dominique Boivin,1,Dagger and Philip E. Branton1,2,*

Departments of Biochemistry1 and Oncology,2 McGill University, Montreal, Quebec, Canada H3G 1Y6

Received 18 May 2000/Accepted 10 October 2000

Complexes containing adenovirus E4orf6 and E1B55K proteins play critical roles in productive infection. Both proteins interact directly with the cellular tumor suppressor p53, and in combination they promote its rapid degradation. To examine the mechanism of this process, degradation of exogenously expressed p53 was analyzed in p53-null human cells infected with adenovirus vectors encoding E4orf6 and/or E1B55K. Coexpression of E4orf6 and E1B55K greatly reduced both the level and the half-life of wild-type p53. No effect was observed with the p53-related p73 proteins, which did not appear to interact with E4orf6 or E1B55K. Mutant forms of p53 were not degraded if they could not efficiently bind E1B55K, suggesting that direct interaction between p53 and E1B55K may be required. Degradation of p53 was independent of both MDM2 and p19ARF, regulators of p53 stability in mammalian cells, but required an extended region of E4orf6 from residues 44 to 274, which appeared to possess three separate biological functions. First, residues 39 to 107 were necessary to interact with E1B55K. Second, an overlapping region from about residues 44 to 218 corresponded to the ability of E4orf6 to form complexes with cellular proteins of 19 and 14 kDa. Third, the nuclear retention signal/amphipathic arginine-rich alpha -helical region from residues 239 to 253 was required. Interestingly, neither the E4orf6 nuclear localization signal nor the nuclear export signal was essential. These results suggested that if nuclear-cytoplasmic shuttling is involved in this process, it must involve another export signal. Degradation was significantly blocked by the 26S proteasome inhibitor MG132, but unlike the HPV E6 protein, E4orf6 and E1B55K were unable to induce p53 degradation in vitro in reticulocyte lysates. Thus, this study implies that the E4orf6-E1B55K complex may direct p53 for degradation by a novel mechanism.

* Corresponding author. Mailing address: Departments of Biochemistry and Oncology, McGill University, McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada. Phone: (514) 398-8350. Fax: (514) 398-7384. E-mail: branton{at}med.mcgill.ca.

dagger Present address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11274.

Dagger Present address: GeminX Biotechnology Inc., Montreal, Quebec, Canada H2W 2M9.

Journal of Virology, January 2001, p. 699-709, Vol. 75, No. 2
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.2.699-709.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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Copyright © 2001 by the American Society for Microbiology. All rights reserved.