Epstein Barr Virus Nuclear Antigen 3C interacts with and enhances the stability of the c-Myc oncoprotein

Department of Microbiology and Tumor Virology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, 201E Johnson Pavilion, 3610, Hamilton Walk, Philadelphia, Pennsylvania 19104

^* To whom correspondence should be addressed. Email: erle{at}mail.med.upenn.edu.

	Abstract

Epstein-Barr virus (EBV) was the first human DNA virus to be associated with cancer. Its oncogenic potential was further demonstrated by its ability to transform primary B lymphocytes in vitro. EBV nuclear antigen 3C (EBNA3C) is one of a small subset of latent antigens critical for transformation of human primary B lymphocytes. Although EBNA3C has been shown to modulate several cellular functions, additional targets involved in cellular transformation remain to be explored. EBNA3C can recruit key components of the SCF^Skp2 ubiquitin ligase complex. In this report, we show that EBNA3C residues 130-190 previously shown to bind to the SCF^Skp2 complex can also strongly associate with the c-Myc oncoprotein. Additionally, the interaction of EBNA3C with c-Myc was mapped to the region of c-Myc that includes the highly conserved Skp2 binding domain. Skp2 has been shown to regulate c-Myc stability and has also been shown to function as a co-activator of transcription for c-Myc target genes. We now show that the EBV latent oncoprotein EBNA3C can stabilize c-Myc and that recruitment of both c-Myc and its cofactor Skp2 to c-Myc dependent promoters can enhance c-Myc dependent transcription. This same region of EBNA3C also recruits and modulates the activity of pRb and p27, both major regulators of the mammalian cell cycle. The inclusion of c-Myc in the group of cellular targets modulated by this domain further accentuates the importance of these critical residues of EBNA3C in bypassing the cell cycle checkpoints.