title: Papillomavirus-Associated Tumor Formation Critically Depends on c-Fos Expression Induced by Viral Protein E2 and Bromodomain Protein Brd4.
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.
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Delcuratolo
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Fertey
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Schuetz
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Leiprecht
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hudjetz
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Brodbeck
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Corall
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Dreer
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Roxana Michaela
authors.initials: RM
authors.lastname: Schwab
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Grimm
authors.affiliation: University of Texas Southwestern Medical Center, Simmons Comprehensive Cancer Center, Department of Biochemistry, Department of Pharmacology, Dallas, Texas, United States of America.
authors.forename: Shwu-Yuan
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Stubenrauch
authors.affiliation: University of Texas Southwestern Medical Center, Simmons Comprehensive Cancer Center, Department of Biochemistry, Department of Pharmacology, Dallas, Texas, United States of America.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.affiliation: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Iftner
mesh_terms: D000818:Animals; D002460:Cell Line; D002472:Cell Transformation, Viral / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D005814:Genes, Viral; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D011817:Rabbits; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D016760:Proto-Oncogene Proteins c-fos; D014157:Transcription Factors; C076036:oncogene protein E2, Human papillomavirus type 1