Abstract
Human Papillomavirus Viruses (HPVs) are associated with the majority of human cervical and anal cancers and 10-30% of head and neck squamous carcinomas. E6 oncoprotein from high risk HPVs interacts with the p53 tumor suppressor protein to facilitate its degradation and increases telomerase activity for extending the life span of host cells. We published previously that the Myc cellular transcription factor associates with the high-risk HPV E6 protein in vivo and participates in the transactivation of the hTERT promoter. In the present study, we further analyzed the role of E6 and the Myc-Max-Mad network in regulating the hTERT promoter. We confirmed that E6 and Myc interact independently and that Max can also form a complex with E6. However, the E6/Max complex is observed only in the presence of Myc, suggesting that E6 associates with Myc/Max dimers. Consistent with the hypothesis that Myc is required for E6 induction of the hTERT promoter, Myc antagonists (Mad or Mnt) significantly blocked E6-mediated transactivation of the hTERT promoter. Analysis of Myc mutants demonstrated that both the transactivation domain and HLH domain of Myc protein were required for binding E6 and for the consequent transactivation of the hTERT promoter, by either Myc or E6. We also showed that E6 increased phosphorylation of Pol II on the hTERT promoter and induced epigenetic histone modifications of the hTERT promoter. More important, knockdown of Myc expression dramatically decreased engagement of acetyl-histones and Pol II at the hTERT promoter in E6-expressing cells. Thus, E6/Myc interaction triggers the transactivation of the hTERT promoter by modulating both histone modifications, Pol II phosphorylation and promoter engagement, suggesting a novel mechanism for telomerase activation and a new target for HPV- associated human cancer.
Highlights
The E6 oncoprotein of a high risk human papillomavirus type 16 (HPV16) has been shown to activate telomerase activity in epithelial cell types predominantly by inducing transcription of the human telomerase reverse transcriptase (hTERT) gene [1,2,3,4,5,6]
We have previously shown that AU1-tagged Human Papillomavirus Viruses (HPVs) E6 associates with Myc oncoprotein in COS cells and primary human foreskin keratinocytes (HFKs) [19]
We confirmed previous published data that E6 and Myc associate in vitro and in vivo [2, 19]. We demonstrated that both the transactivation domain and HLH domain of Myc were required for E6/Myc association and these domains were required for transactivation of the hTERT promoter, by either Myc or E6
Summary
The E6 oncoprotein of a high risk human papillomavirus type 16 (HPV16) has been shown to activate telomerase activity in epithelial cell types predominantly by inducing transcription of the hTERT (human telomerase reverse transcriptase) gene [1,2,3,4,5,6]. E6 can immortalize a subpopulation of human mammary epithelial cells [7,8,9], and E6 in cooperation with E7 can immortalize primary human foreskin keratinocytes (HFKs) [10, 11] Both hTERT and Myc can substitute for E6 in E6/E7-mediated immortalization of primary HFKs [7, 12], indicating that telomerase activation constitutes a major immortalizing activity of E6. Endogenous Myc is too weak to activate telomerase in HFKs, since we and others have shown that endogenous Myc binds to hTERT promoter without activating transcription in primary HFKs [19]
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