Human papillomavirus E2 protein associates with nuclear receptors to stimulate nuclear receptor- and E2-dependent transcriptional activations in human cervical carcinoma cells

Steroid hormones are proposed to act with human papillomaviruses (HPVs) as cofactors in the etiology of cervical cancer. Steroid hormone-activated nuclear receptors (NRs) are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA to either increase or suppress transcription of dependent genes. HPV-induced immortalization of epithelial cells usually requires integration of the viral DNA into the host cell genome. The integration event causes disruption of the E2 gene: the E2 protein is a transcription factor that regulates expression of the E6 and E7 oncoproteins by binding to four sites within the viral long control region (LCR). Our previous study suggested that E6 and E7 oncoproteins both directly bind to some NRs and serve as their cofactors. Here, we provide several lines of evidence demonstrating that the E2 protein is an NR coactivator through its physical interaction with NRs. In our study, the NR coactivator function of HPV E2 protein in human cervical carcinoma cells was independent of the type of E2, HPV transformation and the p53 status. Our observations also provide evidence suggesting regulatory mechanisms for the LCR involving interaction between the E2 protein and NRs in HeLa cells.