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M410343200v1
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Papers In Press, published online ahead of print January 17, 2005
J. Biol. Chem, 10.1074/jbc.M410343200
Submitted on September 9, 2004
Revised on December 10, 2004
Accepted on January 17, 2005

The E6-AP 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 Tomaic, Melissa L. Kelley, Carl C. Baker, Jon Huibregtse, and Richard Schlegel

Pathology Dept., Georgetown University Medical School, Washington, MD 20850

Corresponding Author: schleger{at}georgetown.edu

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 (HPVs) 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 E6-AP, an 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 E6-AP are also defective for increasing telomerase activity and transactivating the hTERT promoter. More importantly, E6-AP knockout mouse cells and siRNA techniques demonstrated that E6-AP was required for hTERT promoter transactivation in both mouse and human cells. Neither E6 nor E6-AP 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/E6-AP 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.


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