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Molecular and Cellular Biology, November 2004, p. 9619-9629, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9619-9629.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Both BC-Box Motifs of Adenovirus Protein E4orf6 Are Required To Efficiently Assemble an E3 Ligase Complex That Degrades p53

Paola Blanchette,1 Chi Ying Cheng,1 Qin Yan,2,3 Gary Ketner,4 David A. Ornelles,5 Thomas Dobner,6 Ronald C. Conaway,2,7 Joan Weliky Conaway,2,3,7 and Philip E. Branton1,8,9*

Departments of Biochemistry,1 Oncology,8 McGill Cancer Centre, McGill University, Montreal, Quebec, Canada,9 Stowers Institute for Medical Research, Kansas City, Missouri,2 Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma,3 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas,7 Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore, Maryland,4 Department of Microbiology and Immunology, School of Medicine, Wake Forest University, Winston-Salem, North Carolina,5 Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensburg, Regensburg, Germany6

Received 12 May 2004/ Returned for modification 15 June 2004/ Accepted 22 July 2004

Small DNA tumor viruses typically encode proteins that either inactivate or degrade p53. Human adenoviruses encode products, including E4orf6 and E1B55K, that do both. Each independently binds to p53 and inhibits its ability to activate gene expression; however, in combination they induce p53 degradation by the ubiquitin pathway. We have shown previously that p53 degradation relies on interactions of E4orf6 with the cellular proteins Cul5, Rbx1, and elongins B and C to form an E3 ligase similar to the SCF and VBC complexes. Here we show that, like other elongin BC-interacting proteins, including elongin A, von Hippel-Lindau protein, and Muf1, the interaction of E4orf6 is mediated by the BC-box motif; however, E4orf6 uniquely utilizes two BC-box motifs for degradation of p53 and another target, Mre11. In addition, our data suggest that the interaction of E1B55K with E4orf6 depends on the ability of E4orf6 to form the E3 ligase complex and that such complex formation may be required for all E4orf6-E1B55K functions.

* Corresponding author. Mailing address: McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6. Phone: (514) 398-7263. Fax: (514) 398-8845. E-mail: philip.branton{at}mcgill.ca.

Molecular and Cellular Biology, November 2004, p. 9619-9629, Vol. 24, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.21.9619-9629.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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