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Journal of Virology, April 2007, p. 3786-3796, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02007-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

NFX1-123 and Poly(A) Binding Proteins Synergistically Augment Activation of Telomerase in Human Papillomavirus Type 16 E6-Expressing Cells{triangledown}

Rachel A. Katzenellenbogen,1,3* Erin M. Egelkrout,1 Portia Vliet-Gregg,3 Lindy C. Gewin,1 Philip R. Gafken,2 and Denise A. Galloway1

Division of Human Biology,1 Division of Proteomics, Fred Hutchinson Cancer Research Center, Seattle, Washington,2 Department of Pediatrics, University of Washington, Seattle, Washington3

Received 14 September 2006/ Accepted 18 January 2007

Overcoming senescence signals in somatic cells is critical to cellular immortalization and carcinogenesis. High-risk human papillomavirus (HPV) can immortalize epithelial cells in culture through degradation of the retinoblastoma protein by HPV E7 and activation of hTERT transcription, the catalytic subunit of telomerase, by the heterodimer HPV E6/E6-associated protein (E6AP). Recent work in our laboratory identified a novel repressor of hTERT transcription, NFX1-91, which is targeted for ubiquitin-mediated degradation by HPV type 16 (HPV16) E6/E6AP. In contrast, NFX1-123, a splice variant NFX1, increased expression from an hTERT promoter that was activated by HPV16 E6/E6AP. Here, we show that HPV16 E6 bound both NFX1-91 and NFX1-123 through the common central domain of NFX1 in the absence of E6AP. NFX1-123 positively regulated hTERT expression, as its knockdown decreased hTERT mRNA levels and telomerase activity and its overexpression increased telomerase activity. We identified new protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) that interacted with NFX1-123 through its N-terminal PAM2 motif, a protein domain characteristic of other PABPC protein partners. Furthermore, NFX1-123 and PABPCs together had a synergistic stimulatory effect on hTERT-regulated reporter assays. The data suggest that NFX1-123 is integral to hTERT regulation in HPV16 E6-expressing epithelial cells and that the interaction between NFX1-123 and PABPCs is critical to hTERT activity.

* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, C1-015, Seattle, WA 98109. Phone: (206) 667-4507. Fax: (206) 667-5185. E-mail: rkatzen{at}u.washington.edu

{triangledown} Published ahead of print on 31 January 2007.

Journal of Virology, April 2007, p. 3786-3796, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02007-06
Copyright © 2007, 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]  
  • Bedard, K. M., Underbrink, M. P., Howie, H. L., Galloway, D. A. (2008). The E6 Oncoproteins from Human Betapapillomaviruses Differentially Activate Telomerase through an E6AP-Dependent Mechanism and Prolong the Lifespan of Primary Keratinocytes. J. Virol. 82: 3894-3902 [Abstract] [Full Text]  
  • Bellon, M., Nicot, C. (2008). Regulation of Telomerase and Telomeres: Human Tumor Viruses Take Control. JNCI J Natl Cancer Inst 100: 98-108 [Abstract] [Full Text]  
  • Sekaric, P., Cherry, J. J., Androphy, E. J. (2008). Binding of Human Papillomavirus Type 16 E6 to E6AP Is Not Required for Activation of hTERT. J. Virol. 82: 71-76 [Abstract] [Full Text]  


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