![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
RESEARCH PAPER
1 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 2 Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 98125, USA
The critical immortalizing activity of the human papillomavirus (HPV) type-16 E6 oncoprotein is to induce expression of hTERT, the catalytic and rate-limiting subunit of telomerase. Additionally, E6 binds to a cellular protein called E6-associated protein (E6-AP) to form an E3 ubiquitin ligase that targets p53 for proteasome-dependent degradation. Although telomerase induction and p53 degradation are separable and distinct functions of E6, binding of E6 to E6-AP strongly correlated with the induction of hTERT. Here, we demonstrate using shRNAs to reduce E6-AP expression that E6-AP is required for E6-mediated telomerase induction. A yeast two-hybrid screen to find new targets of the E6/E6-AP E3 ubiquitin ligase complex identified NFX1. Two isoforms of NFX1 were found: NFX1-123, which coactivated with c-Myc at the hTERT promoter, and NFX1-91, which repressed the hTERT promoter. NFX1-91 was highly ubiquitinated and destabilized in epithelial cells expressing E6. Furthermore, knockdown of NFX1-91 by shRNA resulted in derepression of the endogenous hTERT promoter and elevated levels of telomerase activity. We propose that the induction of telomerase by the HPV-16 E6/E6-AP complex involves targeting of NFX1-91, a newly identified repressor of telomerase, for ubiquitination and degradation.
[Keywords: Telomerase; HPV; transcriptional repressor; ubiquitin; E6; E6-AP]
Received April 23, 2004; revised version accepted July 21, 2004.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1214704.
3 Corresponding author.
E-MAIL dgallowa{at}fhcrc.org; FAX (206) 667-5815.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Xu, W. Luo, D. J. Elzi, C. Grandori, and D. A. Galloway NFX1 Interacts with mSin3A/Histone Deacetylase To Repress hTERT Transcription in Keratinocytes Mol. Cell. Biol., August 1, 2008; 28(15): 4819 - 4828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Bedard, M. P. Underbrink, H. L. Howie, and D. A. Galloway The E6 Oncoproteins from Human Betapapillomaviruses Differentially Activate Telomerase through an E6AP-Dependent Mechanism and Prolong the Lifespan of Primary Keratinocytes J. Virol., April 15, 2008; 82(8): 3894 - 3902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. Harris IV, M. E. Anderson, and J. H. Lee The Effect of Proteasome Inhibition on p53 Degradation and Proliferation in Tonsil Epithelial Cells Arch Otolaryngol Head Neck Surg, February 1, 2008; 134(2): 157 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-S. Gabet, R. Accardi, A. Bellopede, S. Popp, P. Boukamp, B. S. Sylla, J. A. Londono-Vallejo, and M. Tommasino Impairment of the telomere/telomerase system and genomic instability are associated with keratinocyte immortalization induced by the skin human papillomavirus type 38 FASEB J, February 1, 2008; 22(2): 622 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bellon and C. Nicot Regulation of Telomerase and Telomeres: Human Tumor Viruses Take Control J Natl Cancer Inst, January 16, 2008; 100(2): 98 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sekaric, J. J. Cherry, and E. J. Androphy Binding of Human Papillomavirus Type 16 E6 to E6AP Is Not Required for Activation of hTERT J. Virol., January 1, 2008; 82(1): 71 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Topffer, A. Muller-Schiffmann, K. Matentzoglu, M. Scheffner, and G. Steger Protein tyrosine phosphatase H1 is a target of the E6 oncoprotein of high-risk genital human papillomaviruses J. Gen. Virol., November 1, 2007; 88(11): 2956 - 2965. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Teissier, Y. Ben Khalifa, M. Mori, P. Pautier, C. Desaintes, and F. Thierry A New E6/P63 Pathway, Together with a Strong E7/E2F Mitotic Pathway, Modulates the Transcriptome in Cervical Cancer Cells J. Virol., September 1, 2007; 81(17): 9368 - 9376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yugawa, K. Handa, M. Narisawa-Saito, S.-i. Ohno, M. Fujita, and T. Kiyono Regulation of Notch1 Gene Expression by p53 in Epithelial Cells Mol. Cell. Biol., May 15, 2007; 27(10): 3732 - 3742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Katzenellenbogen, E. M. Egelkrout, P. Vliet-Gregg, L. C. Gewin, P. R. Gafken, and D. A. Galloway NFX1-123 and Poly(A) Binding Proteins Synergistically Augment Activation of Telomerase in Human Papillomavirus Type 16 E6-Expressing Cells J. Virol., April 15, 2007; 81(8): 3786 - 3796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Handa, T. Yugawa, M. Narisawa-Saito, S.-i. Ohno, M. Fujita, and T. Kiyono E6AP-Dependent Degradation of DLG4/PSD95 by High-Risk Human Papillomavirus Type 18 E6 Protein J. Virol., February 1, 2007; 81(3): 1379 - 1389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Kelley, K. E. Keiger, C. J. Lee, and J. M. Huibregtse The Global Transcriptional Effects of the Human Papillomavirus E6 Protein in Cervical Carcinoma Cell Lines Are Mediated by the E6AP Ubiquitin Ligase J. Virol., March 15, 2005; 79(6): 3737 - 3747. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Terai, T. Uyama, T. Sugiki, X.-K. Li, A. Umezawa, and T. Kiyono Immortalization of Human Fetal Cells: The Life Span of Umbilical Cord Blood-derived Cells Can Be Prolonged without Manipulating p16INK4a/RB Braking Pathway Mol. Biol. Cell, March 1, 2005; 16(3): 1491 - 1499. [Abstract] [Full Text] [PDF]
|
|
