Human Papilloma Virus 16 E6 Oncoprotein Inhibits Retinoic X Receptor-mediated Transactivation by Targeting Human ADA3 Coactivator

The expression of human papillomavirus (HPV) E6 oncoprotein is causally linked to high-risk HPV-associated human cancers. We have recently isolated hADA3, the human homologue of yeast transcriptional co-activator yADA3, as a novel E6 target. Human ADA3 binds to the high-risk (cancer-associated) but not the low-risk HPV E6 proteins and to immortalization-competent but not to immortalization-defective HPV16 E6 mutants, suggesting a role for the perturbation of hADA3 function in E6-mediated oncogenesis. We demonstrate here that hADA3 directly binds to the retinoic X receptor (RXR)α in vitro and in vivo . Using chromatin immunoprecipitation, we show that hADA3 is part of activator complexes bound to the native RXR response elements within the promoter of the cyclin-dependent kinase inhibitor gene p21. We show that hADA3 enhances the RXRα-mediated sequence-specific transactivation of retinoid target genes, cellular retinoic acid-binding protein II and p21. Significantly, we demonstrate that E6 inhibits the RXRα-mediated transactivation of target genes, implying that perturbation of RXR-mediated transactivation by E6 could contribute to HPV oncogenesis.