Peralta-Zaragoza Oscar, Bermúdez-Morales Víctor, Gutiérrez-Xicotencatl Lourdes, Alcocer-González Juan, Recillas-Targa Félix, Madrid-Marina Vicente
Division of Molecular Biology of Pathogens, National Institute of Public Health, Cuernavaca, Mexico.
Viral Immunol. 2006 Summer;19(3):468-80. doi: 10.1089/vim.2006.19.468.
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-beta1 gene expression and cervical cancer development has been suggested; however, the mechanisms by which HPV influences TGF-beta1 expression remain unclear. In the present study we analyzed the mechanism through which HPV-16 E6 and E7 oncoproteins regulate the TGF-beta1 promoter in cervical tumor cells. Our results showed that E6 and E7 increased TGF-beta1 promoter activity. Furthermore, we identified a specific DNA sequence motif in the TGF-beta1 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-beta1 promoter, and may explain the contribution of HPV-16 to TGF-beta1 gene expression in cervical cancer.
人乳头瘤病毒（HPV）感染是宫颈癌的主要病因，HPV E6和E7癌基因可反式调节许多细胞基因。已有研究表明转化生长因子β1（TGF-β1）基因表达与宫颈癌发展之间存在关联；然而，HPV影响TGF-β1表达的机制仍不清楚。在本研究中，我们分析了HPV-16 E6和E7癌蛋白调节宫颈肿瘤细胞中TGF-β1启动子的机制。我们的结果表明，E6和E7增强了TGF-β1启动子活性。此外，我们在TGF-β1核心启动子中鉴定出一个特定的DNA序列基序，该基序负责反式激活，且与HPV-16 E6和E7癌蛋白相关的Sp1e结合位点相对应。突变分析表明，Sp1e识别位点消除了E6和E7引起的反式激活。这些结果表明病毒癌蛋白与TGF-β1启动子的细胞调节元件之间存在物理相互作用和功能协作，并可能解释HPV-16对宫颈癌中TGF-β1基因表达的作用。
