title: Antioxidant-induced changes of the AP-1 transcription complex are paralleled by a selective suppression of human papillomavirus transcription.
abstract: Considering the involvement of a redox-regulatory pathway in the expression of human papillomaviruses (HPVs), HPV type 16 (HPV-16)-immortalized human keratinocytes were treated with the antioxidant pyrrolidine-dithiocarbamate (PDTC). PDTC induces elevated binding of the transcription factor AP-1 to its cognate recognition site within the viral regulatory region. Despite of increased AP-1 binding, normally indispensable for efficient HPV-16 transcription, viral gene expression was selectively suppressed at the level of initiation of transcription. Electrophoretic mobility supershift assays showed that the composition of the AP-1 complex, predominantly consisting of Jun homodimers in untreated cells, was altered. Irrespective of enhanced c-fos expression, c-jun was phosphorylated and became primarily heterodimerized with fra-1, which was also induced after PDTC incubation. Additionally, there was also an increased complex formation between c-jun and junB. Because both fra-1 and junB overexpression negatively interferes with c-jun/c-fos trans-activation of AP-1-responsive genes, our results suggest that the observed block in viral transcription is mainly the consequence of an antioxidant-induced reconstitution of the AP-1 transcription complex. Since expression of the c-jun/c-fos gene family is tightly regulated during cellular differentiation, defined reorganization of a central viral transcription factor may represent a novel mechanism controlling the transcription of pathogenic HPVs during keratinocyte differentiation and in the progression to cervical cancer.
authors.affiliation: Forschungsschwerpunkt Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Heidelberg, Germany. f.roesl@dkfz-heidelberg.de
authors.forename: F
authors.initials: F
authors.lastname: Rösl
authors.forename: B C
authors.initials: BC
authors.lastname: Das
authors.forename: M
authors.initials: M
authors.lastname: Lengert
authors.forename: K
authors.initials: K
authors.lastname: Geletneky
authors.forename: H
authors.initials: H
authors.lastname: zur Hausen
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D015536:Down-Regulation; D016158:Genes, p53; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D027383:Papillomaviridae / Q000235:genetics*; D011759:Pyrrolidines / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000187:drug effects* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011759:Pyrrolidines; D013859:Thiocarbamates; D018808:Transcription Factor AP-1; C020972:pyrrolidine dithiocarbamic acid