ANTIOXIDANT-INDUCED CHANGES OF THE AP-1 TRANSCRIPTION COMPLEX ARE PARALLELED BY A SELECTIVE SUPPRESSION OF HUMAN PAPILLOMAVIRUS TRANSCRIPTION

Considering the involvement of a redox-regulatory pathway in the expre ssion of human papillomaviruses (HPVs), HPV type 16 (HPV-16)-immortali zed human keratinocytes were treated with the antioxidant pyrrolidine- dithiocarbamate (PDTC), PDTC induces elevated binding of the transcrip tion factor AP-1 to its cognate recognition site within the viral regu latory region, Despite of increased AP-1 binding, normally indispensab le for efficient HPV-16 transcription, viral gene expression was selec tively suppressed at the level of initiation of transcription. Electro phoretic 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, wh ich was also induced after PDTC incubation, Additionally, there was al so 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 th e observed block in viral transcription is mainly the consequence of a n 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 differentiat ion and in the progression to cervical cancer.