E6 and E7 Oncoproteins from Human Papillomavirus Type 16 Induce Activation of Human Transforming Growth Factor beta sub(1) Promoter throughout Sp1 Recognition Sequence

Human Papillomavirus (HPV) infection is the main etiologic agent of cervical cancer and HPV E6 and E7 oncogenes trans-regulate many cellular genes. An association between TGF- beta sub(1) gene expression and cervical cancer development has been suggested; however, the mechanisms by which HPV influences TGF- beta sub(1) expression remain unclear. In the present study we analyzed the mechanism through which HPV-16 E6 and E7 oncoproteins regulate the TGF- beta sub(1) promoter in cervical tumor cells. Our results showed that E6 and E7 increased TGF- beta sub(1) promoter activity. Furthermore, we identified a specific DNA sequence motif in the TGF- beta sub(1) core promoter that is responsible for trans-activation and that corresponds to the Sp1e-binding site associated with HPV-16 E6 and E7 oncoproteins. Mutational analysis showed that the Sp1e recognition site abolished the trans-activation caused by E6 and E7. These results suggest a physical interaction and functional cooperation between viral oncoproteins and cellular regulatory elements of the TGF- beta sub(1) promoter, and may explain the contribution of HPV-16 to TGF- beta sub(1) gene expression in cervical cancer.