Silencing of integrated human papillomavirus type 18 oncogene transcription in cells expressing SerpinB2.
The serine protease inhibitor SerpinB2 (PAI-2), a major product of differentiating squamous epithelial cells, has recently been shown to bind and protect the retinoblastoma protein (Rb) from degradation. In human papillomavirus type 18 (HPV-18)-transformed epithelial cells the expression of the E6 and E7 oncoproteins is controlled by the HPV-18 upstream regulatory region (URR). Here we illustrate that PAI-2 expression in the HPV-18-transformed cervical carcinoma line HeLa resulted in the restoration of Rb expression, which led to the functional silencing of transcription from the HPV-18 URR. This caused loss of E7 protein expression and restoration of multiple E6- and E7-targeted host proteins, including p53, c-Myc, and c-Jun. Rb expression emerged as sufficient for the transcriptional repression of the URR, with repression mediated via the C/EBPbeta-YY1 binding site (URR 7709 to 7719). In contrast to HeLa cells, where the C/EBPbeta-YY1 dimer binds this site, in PAI-2- and/or Rb-expressing cells the site was occupied by the dominant-negative C/EBPbeta isoform liver-enriched transcriptional inhibitory protein (LIP). PAI-2 expression thus has a potent suppressive effect on HPV-18 oncogene transcription mediated by Rb and LIP, a finding with potential implications for prognosis and treatment of HPV-transformed lesions.
Darnell
Grant A
GA
Queensland Institute of Medical Research, University of Queensland, Brisbane, Queensland, Australia.
Antalis
Toni M
TM
Rose
Barbara R
BR
Suhrbier
Andreas
A
D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics*; D027383:Papillomaviridae / Q000235:genetics*; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D016160:Retinoblastoma Protein / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D022782:CCAAT-Enhancer-Binding Protein-beta; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; C489427:MYC protein, human; D009856:Oncogene Proteins, Viral; D017396:Plasminogen Activator Inhibitor 2; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53