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Molecular and Cellular Biology, August 2008, p. 4819-4828, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.01969-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

NFX1 Interacts with mSin3A/Histone Deacetylase To Repress hTERT Transcription in Keratinocytes{triangledown}

Mei Xu,1,3,{dagger} Weifeng Luo,1,{dagger},{ddagger} David J. Elzi,2,3,§ Carla Grandori,1,¶ and Denise A. Galloway1*

Divisions of Human Biology,1 Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,2 Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington 981953

Received 31 October 2007/ Returned for modification 11 December 2007/ Accepted 12 May 2008

Transcription of the catalytic subunit of telomerase (hTERT) in keratinocytes can be induced by human papillomavirus type 16 (HPV16) E6/E6AP ubiquitin ligase through degradation of the repressor, NFX1-91. Here, we demonstrate that NFX1-91 interacts with the corepressor complex mSin3A/histone deacetylase (HDAC) at the hTERT promoter. By degrading NFX1-91, E6/E6AP changes the chromatin structure at the hTERT promoter as indicated by enhanced acetylation of histones H3 and H4 as well as dimethylation of H3K4. Knockdown of NFX1-91 by short hairpin RNA (shRNA) mimics the effect of E6 and leads to acetylation of histones H3 and H4. Conversely, knockdown of E6AP by shRNA suppresses histone acetylation at the hTERT promoter. These data demonstrate that targeted degradation of NFX1-91 by E6/E6AP dissociates the mSin3A/HDAC complex from the hTERT promoter and induces hTERT transcription.

* Corresponding author. Mailing address: Program in Cancer Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., C1-015, Seattle, WA 98109-1024. Phone: (206) 667-4500. Fax: (206) 667-5815. E-mail: dgallowa{at}fhcrc.org

{triangledown} Published ahead of print on 27 May 2008.

{dagger} M.X. and W.L. contributed equally to this paper.

{ddagger} Present address: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232.

§ Present address: Department of Surgery, School of Medicine, University of Colorado and Bonfils Blood Center, Denver, CO 80230.

Present address: Rosetta Inpharmatics, 401 Terry Avenue N., Seattle, WA 98109.

Molecular and Cellular Biology, August 2008, p. 4819-4828, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.01969-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Katzenellenbogen, R. A., Vliet-Gregg, P., Xu, M., Galloway, D. A. (2009). NFX1-123 Increases hTERT Expression and Telomerase Activity Posttranscriptionally in Human Papillomavirus Type 16 E6 Keratinocytes. J. Virol. 83: 6446-6456 [Abstract] [Full Text]  


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