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J. Biol. Chem., Vol. 280, Issue 11, 10807-10816, March 18, 2005

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The E6AP Ubiquitin Ligase Is Required for Transactivation of the hTERT Promoter by the Human Papillomavirus E6 Oncoprotein^*

Xuefeng Liu, Hang Yuan, Baojin Fu, Gary L. Disbrow, Tania Apolinario, Vjekoslav Tomai, Melissa L. Kelley¶, Carl C. Baker, Jon Huibregtse¶, and Richard Schlegel||

From the Department of Pathology and Oncology, Georgetown University Medical School, Washington, D. C. 20057, the Laboratory of Cellular Oncology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, and the ^¶Institute for Cellular and Molecular Biology, Section of Molecular Genetics and Microbiology, University of Texas, Austin, Texas 78712

Most human cancer cells display increased telomerase activity that appears to be critical for continued cell proliferation and tumor formation. The E6 protein of malignancy-associated human papillomaviruses increases cellular telomerase in primary human keratinocytes at least partly via transcriptional activation of the telomerase catalytic subunit, hTERT. In the present study, we investigated whether E6AP, a ubiquitin ligase well known for binding and mediating some of the activities of the E6 oncoprotein, participated in the transactivation of the hTERT promoter. Our results demonstrate that E6 mutants that fail to bind E6AP are also defective for increasing telomerase activity and transactivating the hTERT promoter. More importantly, E6AP knock-out mouse cells and small interfering RNA techniques demonstrated that E6AP was required for hTERT promoter transactivation in both mouse and human cells. Neither E6 nor E6AP bound to the hTERT promoter or activated the promoter in the absence of the partner protein. With all transactivation-competent E6 proteins, induction of the hTERT promoter was dependent upon E box elements in the core promoter. It appears, therefore, that E6-mediated activation of the hTERT promoter requires a complex of E6-E6AP to engage the hTERT promoter and that activation is dependent upon Myc binding sites in the promoter. The recruitment of a cellular ubiquitin ligase to the hTERT promoter during E6-mediated transcriptional activation suggests a role for the local ubiquitination (and potential degradation) of promoter-associated regulatory proteins, including the Myc protein.

Received for publication, September 9, 2004 , and in revised form, December 10, 2004.

^* This work was supported by National Institutes of Health Grants R01CA106440 and R01CA53371 (to R. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Pathology, Georgetown University Medical Center, 3900 Reservoir Rd. NW, Washington, D. C. 20057. Tel.: 202-687-1704; Fax: 202-687-8934; E-mail: schleger{at}georgetown.edu.

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