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J. Virol. doi:10.1128/JVI.02466-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

hAda3 degradation by papillomavirus 16 E6 correlates with abrogation of p14ARF-p53 pathway and efficient immortalization of human mammary epithelial cells

Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA

^* To whom correspondence should be addressed. Email: elliot.androphy{at}umassmed.edu.

	Abstract

Two activities of human papillomaviruses (HPV) type 16 E6 are proposed to contribute to efficient immortalization of human epithelial cells: degradation of p53 protein and induction of telomerase. However, the requirement for p53 inactivation has been debated. Another E6 target is the hAda3 protein, a p53 co-activator and a component of histone acetyltransferase complexes. We have previously described the role of hAda3 and p53 acetylation in p14ARF induced human mammary epithelial cells (MEC) senescence (Sekaric et al 2007). In this study, we analyzed a set of HPV 16 E6 mutants for ability to induce hAda3 degradation. E6 mutants that degrade hAda3 but not p53 could abrogate p14ARF-induced growth arrest despite the presence of normal levels of p53, and efficiently immortalized MECs. However, two E6 mutants that were previously reported to immortalize MECs with low efficiency were found to be defective for both p53 and hAda3 degradation. We found that these immortal MECs select for reduced p53 protein levels through a proteasome dependent mechanism. The findings strongly imply that inactivation of the p14ARF-p53 pathway, whether by E6 mediated degradation of p53 or hAda3 or cellular adaptation is required for MEC immortalization.