title: Papillomavirus E2 protein induces expression of the matrix metalloproteinase-9 via the extracellular signal-regulated kinase/activator protein-1 signaling pathway.
abstract: Papillomaviruses are involved in the development of cancers of the female cervix, head and neck, and skin. An excellent model to study papillomavirus-induced tumor induction and progression is the New Zealand White rabbit, where the skin is infected with the cottontail rabbit papillomavirus (CRPV). This leads to the formation of benign tumors that progress into invasive and metastasizing carcinomas without the need for cofactors. We have shown previously that specific mutations in the transactivation domain of the transcription/replication factor E2 cause a dramatic loss in the tumor induction efficiency of the viral genome and a major deficiency in tumor progression as we show now. By comparing wild-type (WT) and mutant E2-induced skin tumors, we found high levels of matrix metalloproteinase-9 (MMP-9) protein and transcripts in WT CRPV-E2-induced tumors in contrast to certain mutant CRPV-E2-induced papillomas and normal uninfected skin. Stable cell lines and reporter assays revealed that E2 from different papillomavirus types is able to transactivate the MMP-9 promoter via the promoter-proximal activator protein-1 (AP-1) site as shown in reporter gene assays with mutant MMP-9 promoter constructs. Furthermore, WT E2 but not mutant E2 strongly transactivated a minimal promoter reporter construct with multiple AP-1 sites. The MMP-9 protein induced in cells expressing E2 degrades collagen matrices as measured in Matrigel-based invasion/mobility assays. E2-induced MMP-9 expression can be blocked by a chemical inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase 1 (PD 098059), suggesting that E2 activates the MAPK/ERK signaling pathway, which is further supported by the induction of ERK1 in CRPV-E2-transfected cells.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University Hospital of Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Behren
authors.forename: Christian
authors.initials: C
authors.lastname: Simon
authors.forename: Roxana Michaela
authors.initials: RM
authors.lastname: Schwab
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Loetzsch
authors.forename: Stephan
authors.initials: S
authors.lastname: Brodbeck
authors.forename: Evamaria
authors.initials: E
authors.lastname: Huber
authors.forename: Frank
authors.initials: F
authors.lastname: Stubenrauch
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Zenner
authors.forename: Thomas
authors.initials: T
authors.lastname: Iftner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D012777:Cottontail rabbit papillomavirus / Q000472:pathogenicity / Q000502:physiology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010212:Papilloma / Q000503:physiopathology / Q000821:virology*; D030361:Papillomavirus Infections / Q000503:physiopathology / Q000821:virology; D011401:Promoter Regions, Genetic; D011817:Rabbits; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000821:virology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology*; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000235:genetics / Q000494:pharmacology*
chemical_list: C422983:E2 protein, Cottontail rabbit papillomavirus; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014764:Viral Proteins; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9