E6 and E7 Oncoproteins from Human Papillomavirus Type 16 Induce Activation of Human Transforming Growth Factor β 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-β ₁ gene expression and cervical cancer development has been suggested; however, the mechanisms by which HPV influences TGF-β ₁ expression remain unclear. In the present study we analyzed the mechanism through which HPV-16 E6 and E7 oncoproteins regulate the TGF-β ₁ promoter in cervical tumor cells. Our results showed that E6 and E7 increased TGF-β ₁ promoter activity. Furthermore, we identified a specific DNA sequence motif in the TGF-β ₁ core promoter that is responsible fortrans-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-β ₁ promoter, and may explain the contribution of HPV-16 to TGF-β ₁ gene expression in cervical cancer.