HUMAN PAPILLOMAVIRUS TYPE-16 E6 PROTEIN TRANSCRIPTIONALLY MODULATES FIBRONECTIN GENE-EXPRESSION BY INDUCTION OF PROTEIN COMPLEXES BINDING TO THE CYCLIC-AMP RESPONSE ELEMENT

Although human papillomavirus type 16 (HPV16) E6 protein has a transcr iption-modulatory activity for a wide variety of viral promoters, a ce llular target for this activity of E6 has not Set been identified, In this study, using differential hybridization, we identified a mouse fi bronectin (FN) gene as a putative cellular target whose expression is up-regulated by E6. Chloramphenicol acetyltransferase (CAT) assays wit h mouse and rat FN promoter-CAT fusion constructs indicated that HPV16 E6 transactivates the FN promoters in a p53-independent manner, Delet ion and site-specific mutation analyses revealed that transactivation by HPV16 E6 depends upon a cyclic AMP response element (CRE) located a t -160 relative to the start site of transcription. Gel retardation as says demonstrated that nuclear extracts from the HPV16 E6-expressing c ells, compared to those from parental 10T1/2 cells, have increased bin ding activity to the CRE, Antibodies against c-Jun and ATF-2 disrupted this binding activity. These data indicate that HPV16 E6 transcriptio nally modulates FN gene expression via the CRE by inducing the binding of the protein complexes, probably including c-Jun and ATF-2, to the CRE.