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

Maria Delcuratolo, Jasmin Fertey, Markus Schneider, Johanna Schuetz, Natalie Leiprecht, Benjamin Hudjetz, Stephan Brodbeck, Silke Corall, Marcel Dreer, Roxana Michaela Schwab, Martin Grimm, Shwu Yuan Wu, Frank Stubenrauch, Cheng Ming Chiang, Thomas Iftner

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere1005366
JournalPLoS Pathogens
Volume12
Issue number1
DOIs
StatePublished - 2016

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Viral Proteins
Oncogenes
RNA Interference
Carcinogenesis
Transcription Factors
Binding Sites
Neoplasms
Proteins
Chromatin Immunoprecipitation
Transcription Factor AP-1
Gene Expression Profiling
Protein Binding
Statistical Factor Analysis
Cell Line
Skin
Mutation

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Delcuratolo, M., Fertey, J., Schneider, M., Schuetz, J., Leiprecht, N., Hudjetz, B., ... Iftner, T. (2016). Papillomavirus-Associated Tumor Formation Critically Depends on c-Fos Expression Induced by Viral Protein E2 and Bromodomain Protein Brd4. PLoS Pathogens, 12(1), [e1005366]. https://doi.org/10.1371/journal.ppat.1005366

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

In: PLoS Pathogens, Vol. 12, No. 1, e1005366, 2016.

Research output: Contribution to journalArticle

Delcuratolo, M, Fertey, J, Schneider, M, Schuetz, J, Leiprecht, N, Hudjetz, B, Brodbeck, S, Corall, S, Dreer, M, Schwab, RM, Grimm, M, Wu, SY, Stubenrauch, F, Chiang, CM & Iftner, T 2016, 'Papillomavirus-Associated Tumor Formation Critically Depends on c-Fos Expression Induced by Viral Protein E2 and Bromodomain Protein Brd4', PLoS Pathogens, vol. 12, no. 1, e1005366. https://doi.org/10.1371/journal.ppat.1005366
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. / Papillomavirus-Associated Tumor Formation Critically Depends on c-Fos Expression Induced by Viral Protein E2 and Bromodomain Protein Brd4. In: PLoS Pathogens. 2016 ; Vol. 12, No. 1.
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abstract = "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.",
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AU - Schuetz, Johanna

AU - Leiprecht, Natalie

AU - Hudjetz, Benjamin

AU - Brodbeck, Stephan

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AU - Dreer, Marcel

AU - Schwab, Roxana Michaela

AU - Grimm, Martin

AU - Wu, Shwu Yuan

AU - Stubenrauch, Frank

AU - Chiang, Cheng Ming

AU - Iftner, Thomas

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