Papillomavirus-Associated Tumor Formation Critically Depends on c-Fos Expression Induced by Viral Protein E2 and Bromodomain Protein Brd4

• Published in: PLoS pathogens 2016-01, Vol.12 (1), p.e1005366-e1005366
• Main Authors: Delcuratolo, Maria, Fertey, Jasmin, Schneider, Markus, Schuetz, Johanna, Leiprecht, Natalie, Hudjetz, Benjamin, Brodbeck, Stephan, Corall, Silke, Dreer, Marcel, Schwab, Roxana Michaela, Grimm, Martin, Wu, Shwu-Yuan, Stubenrauch, Frank, Chiang, Cheng-Ming, Iftner, Thomas
• Format: Article
• Language: English
• Subjects: Animals; Binding sites; Cell Line; Cell Transformation, Viral - physiology; Chromatin Immunoprecipitation; Disease Models, Animal; DNA Mutational Analysis; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Electrophoretic Mobility Shift Assay; Gene expression; Gene Expression Regulation, Viral - physiology; Genes; Genes, Viral; Genetic aspects; Health aspects; Host-virus relationships; Immunoprecipitation; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Observations; Oncogene Proteins, Viral - genetics; Oncogene Proteins, Viral - metabolism; Oncogenes; Papillomaviridae; Papillomavirus Infections - complications; Papillomavirus Infections - genetics; Papillomavirus Infections - metabolism; Papillomaviruses; Protein binding; Proto-Oncogene Proteins c-fos - biosynthesis; Proto-Oncogene Proteins c-fos - genetics; Rabbits; Rodents; Skin cancer; Transcription Factors - genetics; Transcription Factors - metabolism; Viral proteins
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005366

We investigated the mechanism of how the papillomavirus E2 transcription factor can activate promoters through activator protein (AP)1 binding sites. Using an unbiased approach with an inducible cell line expressing the viral transcription factor E2 and transcriptome analysis, we found that E2 induces the expression of the two AP1 components c-Fos and FosB in a Brd4-dependent manner. In vitro RNA interference confirmed that c-Fos is one of the AP1 members driving the expression of viral oncogenes E6/E7. Mutation analysis and in vivo RNA interference identified an essential role for c-Fos/AP1 and also for the bromodomain protein Brd4 for papillomavirus-induced tumorigenesis. Lastly, chromatin immunoprecipitation analysis demonstrated that E2 binds together with Brd4 to a canonical E2 binding site (E2BS) in the promoter of c-Fos, thus activating c-Fos expression. Thus, we identified a novel way how E2 activates the viral oncogene promoter and show that E2 may act as a viral oncogene by direct activation of c-Fos involved in skin tumorigenesis.