The DOI matches its Crossref record; 60 of the 61 references it cites were found in a registry or an index, and 1 are not checked yet; none of the 38 sources its claims cite is checked for support yet.
Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex
Open accessAbstract
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.
Checked 2026-11-12 · 1 reference not checked yet
Overview
CoChat Summary
Written by AI from the paper’s full text.
TL;DR
HPV-16 E6 induces hTERT/telomerase, and this paper shows E6-AP is required for that induction. A yeast two-hybrid screen identified NFX1; its NFX1-91 isoform represses the hTERT promoter and is preferentially bound, ubiquitinated, and destabilized by the E6/E6-AP complex.
Key findings
- E6-AP is required for E6-mediated telomerase induction: shRNA against E6-AP reduced E6-AP RNA to ∼29% of vector control, abrogated E6-mediated p53 degradation, and disrupted E6-mediated hTERT induction and TRAP activity in HFKs.
- NFX1 has two splice isoforms with opposing hTERT promoter activities: NFX1-123 coactivated with c-Myc, whereas NFX1-91 repressed the hTERT promoter, reducing activity to ∼60% of background alone and robustly repressing c-Myc induction.
- NFX1-91 is preferentially targeted by E6/E6-AP: E6 expression reduced NFX1-91 half-life ∼46%, from 2.5 h to 1.3 h; MG-132 restored levels; NFX1-91 was highly ubiquitinated, and E6 coimmunoprecipitated preferentially with NFX1-91 rather than NFX1-123.
- NFX1-91 knockdown derepressed endogenous hTERT and increased telomerase activity; E6-expressing cells with reduced NFX1-91 showed greater than twofold increased hTERT by RT-PCR and TRAP, and reduced E6-AP increased NFX1-91 half-life from 1.2 to 1.7 h.
Methods
- Primary human foreskin keratinocytes (HFKs) and 293T, HeLa, C33A, and U2OS cells were used with retroviral shRNA/expression constructs; a yeast two-hybrid screen used catalytically defective E6-AP C833A plus E6 against fetal brain and HeLa cDNA libraries.
- Functional assays included hTERT luciferase reporter assays (710 and 219 constructs), EMSA with recombinant His-tagged NFX1 fragments, RT-PCR, TRAP telomerase assays, Western blotting, cycloheximide and pulse-chase half-life measurements, immunoprecipitation, in vivo ubiquitination assays, and SAβ-galactosidase staining.
- Analyses compared promoter activity, protein stability, ubiquitination, and telomerase activity across vector, E6, E6 mutant, and shRNA conditions; data are presented as representative experiments or averages with error bars where indicated.
Limitations
- The paper states that NFX1-91 did not overexpress well despite repeated attempts, so the authors could not demonstrate hTERT promoter repression by increased NFX1-91 expression.
- The paper states that the reciprocal coimmunoprecipitation to precipitate AU1-16E6 with NFX1 antibody did not work, and that no significant telomere-length differences were observed despite increased telomerase activity.
- The paper states that whether NFX1-123 coactivation is integral to E6-mediated hTERT induction remains to be tested, and future efforts will determine whether either NFX1 isoform is differentially bound in vivo in E6-expressing cells.
- Evident from the text: several key binding and overexpression results are supported by “data not shown,” and the model relies heavily on transient assays, shRNA knockdown, and primary HFK systems rather than in vivo tumor models.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
48 Own result · 17 Own interpretation · 12 Check pending · 7 No full text of the sources · 3 Own method · 2 Sources not found · 1 Not checked yet
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we demonstrate using shRNAs to reduce E6-AP expression that E6-AP is required for E6-mediated telomerase induction.”
- Also stated in: § Results · boosted
“These experiments demonstrated that E6AP expression was required for hTERT induction by HPV-16 E6.”
boostedstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Results · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additional in vitro E6/ E6-AP binding studies (data not shown), as well as published data (Table 1), revealed a strong correlation between E6 binding to E6-AP and telomerase activation.”
boostedstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NFX1-123 strongly coactivated with c-Myc at the hTERT promoter, whereas NFX1-91 repressed the activity of the promoter.”
boostedstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This gene actually encoded two splice variants, NFX1123 and NFX1-91 , with opposing activities in hTERT reporter assays (Fig. 2).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NFX1-123 strongly coactivated with c-Myc at the hTERT promoter, whereas NFX1-91 repressed the activity of the promoter.”
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 25
- Probably not a substantial claim. 19
- The quote only partly states this claim. 2
Create a free account to see these claims.
Create a free account to see these assumptions.
49 more claims
Create a free account to see all 90 claims and to verify the 20 references still open.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Plasmids
“Briefly, oligos containing the 26- to 29-nt shRNA sequence were used in PCR reactions”
§ Plasmids
“The n91sh construct was targeted to the 3 ′ UTR region (5 ′ -TGTGGAACCAGCCCAACTGCCCATCAGTCAA3 ′ ).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ NFX1-91 binds a putative X box in the proximal promoter of hTERT
“HFK/LXSN and HFK/E6 cells were treated with 25 µg/mL cycloheximide for the indicated time points.”
§ Proteasome inhibition and cycloheximide treatment
“For half-life analysis, HFKs were treated with 25 µM cycloheximide (Calbiochem) and harvested in WE16th lysis buffer at the indicated time points.”
Citations
Cites
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477
A DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,917 · cited 1×
“Cells respond to the chromosome ends as though they are a double-stranded DNA break and generally attempt to repair the exposed chromosome ends or initiate a senescent arrest (Espejel and Blasco 2002; d’Adda di Fagagna et al. 2003; Takai et al. 2003).”
BackgroundCreation of human tumour cells with defined genetic elements
Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., & Weinberg, R. A. (1999) · Nature · doi:10.1038/22780 · Cited by 2,345
The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53
Scheffner, M., Huibregtse, J. M., Vierstra, R. D., & Howley, P. M. (1993) · Cell · doi:10.1016/0092-8674(93)90384-3 · Cited by 2,054
Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cellsPreprint
Paddison, P. J., Caudy, A. A., Bernstein, E., Hannon, G. J., & Conklin, D. S. (2002) · Genes & Development · doi:10.1101/gad.981002 · Cited by 1,571
DNA Damage Foci at Dysfunctional Telomeres
Takai, H., Smogorzewska, A., & de Lange, T. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00542-6 · Cited by 1,409
Hemann, M. T., Strong, M. A., Hao, L.-Y., & Greider, C. W. (2001) · Cell · doi:10.1016/s0092-8674(01)00504-9 · Cited by 1,219
Kiyono, T., Foster, S. A., Koop, J. I., McDougall, J. K., Galloway, D. A., & Klingelhutz, A. J. (1998) · Nature · doi:10.1038/23962 · Cited by 1,206
Self-citationInhibition of telomerase limits the growth of human cancer cells
Hahn, W. C., Stewart, S. A., Brooks, M. W., York, S. G., Eaton, E. N., Kurachi, A. L., Beijersbergen, R. L., Knoll, J. H. M., Meyerson, M. M., & Weinberg, R. A. (1999) · Nature Medicine · doi:10.1038/13495 · Cited by 1,038
RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination
Lorick, K. L., Jensen, J. P., Fang, S., Ong, A. M., Hatakeyama, S., & Weissman, A. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.20.11364 · Cited by 981
Research works printed but not linked: 6
- 1996, Cancer Res., 56, 4620
- 2000, Cancer Res., 60, 537
- 1999, Cancer Res., 59, 6087
- 1999, Cancer Res., 59, 826
- 2000, Clin. Cancer Res., 6, 1239
- 1999, Cancer Res., 59, 551
Cited by
Human Papillomavirus E6 and E7: The Cervical Cancer Hallmarks and Targets for Therapy
Pal, A., & Kundu, R. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.03116 · Cited by 650
Drug discovery in the ubiquitin–proteasome system
Nalepa, G., Rolfe, M., & Harper, J. W. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2056 · Cited by 638
Narisawa‐Saito, M., & Kiyono, T. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00546.x · Cited by 528
Self-citationYuan, X., Larsson, C., & Xu, D. (2019) · Oncogene · doi:10.1038/s41388-019-0872-9 · Cited by 450
The human papillomavirus family and its role in carcinogenesis
Tommasino, M. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.11.002 · Cited by 434
Human Papillomavirus in Head and Neck Cancer: Its Role in Pathogenesis and Clinical Implications
Chung, C. H., & Gillison, M. L. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-0784 · Cited by 422
Papillomavirus E6 oncoproteins
Pol, S. V., & Klingelhutz, A. J. (2013) · Virology · doi:10.1016/j.virol.2013.04.026 · Cited by 374
Howie, H. L., Katzenellenbogen, R. A., & Galloway, D. A. (2008) · Virology · doi:10.1016/j.virol.2008.11.017 · Cited by 349
Self-citationUnderstanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers
Kyo, S., Takakura, M., Fujiwara, T., & Inoue, M. (2008) · Cancer Science · doi:10.1111/j.1349-7006.2008.00878.x · Cited by 347
The biological properties of E6 and E7 oncoproteins from human papillomaviruses
Ghittoni, R., Accardi, R., Hasan, U. A., Gheit, T., Sylla, B. S., & Tommasino, M. (2009) · Virus Genes · doi:10.1007/s11262-009-0412-8 · Cited by 338
Oncogenic activities of human papillomaviruses
McLaughlin-Drubin, M. E., & Münger, K. (2009) · Virus Research · doi:10.1016/j.virusres.2009.06.008 · Cited by 332
Yeo-Teh, N. S. L., Ito, Y., & Jha, S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19061706 · Cited by 297
Thomas, A., Necchi, A., Muneer, A., Tobias‐Machado, M., Tran, A. T. H., Rompuy, A. V., Spiess, P. E., & Albersen, M. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00246-5 · Cited by 280
Scarth, J. A., Patterson, M. R., Morgan, E. L., & Macdonald, A. (2021) · Journal of General Virology · doi:10.1099/jgv.0.001540 · Cited by 250
Yugawa, T., & Kiyono, T. (2009) · Reviews in Medical Virology · doi:10.1002/rmv.605 · Cited by 243
Self-citationMorales‐Sánchez, A., & Fuentes‐Pananá, E. M. (2014) · Viruses · doi:10.3390/v6104047 · Cited by 232
Bhattacharjee, R., Das, S. S., Biswal, S. S., Nath, A., Das, D., Basu, A., Malik, S., Kumar, L., Kar, S., Singh, S. K., et al. (2022) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2022.103675 · Cited by 218
Regulation of Notch1 Gene Expression by p53 in Epithelial Cells
Yugawa, T., Handa, K., Narisawa‐Saito, M., Ohno, S.-I., Fujita, M., & Kiyono, T. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.02119-06 · Cited by 199
Self-citationPapillomavirus E6 and E7 proteins and their cellular targets
Wise-Draper, T. M. (2007) · Frontiers in bioscience · doi:10.2741/2739 · Cited by 185
Nominé, Y., Masson, M., Charbonnier, S., Zanier, K., Ristriani, T., Deryckère, F., Sibler, A.-P., Desplancq, D., Atkinson, R. A., Weiss, E., et al. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.024 · Cited by 177
Klingelhutz, A. J., & Roman, A. (2012) · Virology · doi:10.1016/j.virol.2011.12.018 · Cited by 177
Regulating the human HECT E3 ligases
Sluimer, J., & Distel, B. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2848-2 · Cited by 175
Reiser, J., Hurst, J., Voges, M., Krauss, P., Münch, P., Iftner, T., & Stubenrauch, F. (2011) · Journal of Virology · doi:10.1128/jvi.05279-11 · Cited by 155
Underbrink, M. P., Howie, H. L., Bedard, K., Koop, J. I., & Galloway, D. A. (2008) · Journal of Virology · doi:10.1128/jvi.00902-08 · Cited by 168
Self-citationMammary epithelial cell transformation: Insights from cell culture and mouse models
Dimri, G., Band, H., & Band, V. (2005) · Breast Cancer Research · doi:10.1186/bcr1275 · Cited by 120
Molecular mechanisms of the preventable causes of cancer in the United StatesPreprint
Golemis, E. A., Scheet, P. A., Beck, T. N., Scolnick, E. M., Hunter, D. J., Hawk, E. T., & Hopkins, N. H. (2018) · Genes & Development · doi:10.1101/gad.314849.118 · Cited by 164
Transcription Regulation of the Human Telomerase Reverse Transcriptase (hTERT) Gene
Ramlee, M. K., Wang, J., Toh, W. H., & Li, S. (2016) · Genes · doi:10.3390/genes7080050 · Cited by 161
Pim, D., & Banks, L. (2010) · Apmis · doi:10.1111/j.1600-0463.2010.02618.x · Cited by 156
HPV E6 protein interacts physically and functionally with the cellular telomerase complex
Liu, X., Dakic, A., Zhang, Y., Dai, Y., Chen, R., & Schlegel, R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906357106 · Cited by 156
Recurrent Respiratory Papillomatosis
Venkatesan, N. N., Pine, H. S., & Underbrink, M. P. (2012) · Otolaryngologic Clinics of North America · doi:10.1016/j.otc.2012.03.006 · Cited by 154
Productive Lifecycle of Human Papillomaviruses that Depends Upon Squamous Epithelial Differentiation
Kajitani, N., Satsuka, A., Kawate, A., & Sakai, H. (2012) · Frontiers in Microbiology · doi:10.3389/fmicb.2012.00152 · Cited by 154
Hallmarks of HPV carcinogenesis: The role of E6, E7 and E5 oncoproteins in cellular malignancy
Estêvão, D., Costa, N. R., da Costa, R. M. G., & Medeiros, R. (2019) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2019.01.001 · Cited by 154
Hepatitis C Virus Induces E6AP-Dependent Degradation of the Retinoblastoma Protein
Munakata, T., Liang, Y., Kim, S., McGivern, D. R., Huibregtse, J. M., Nomoto, A., & Lemon, S. M. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030139 · Cited by 152
Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use
Zhang, Y., Qiu, K., Ren, J., Zhao, Y. Q., & Cheng, P. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02083-w · Cited by 150
El‐Mofty, S. K., & Lu, D. W. (2005) · The American Journal of Surgical Pathology · doi:10.1097/01.pas.0000173240.63073.fe · Cited by 150
MicroRNA in Cervical Cancer: OncomiRs and Tumor Suppressor miRs in Diagnosis and Treatment
Banno, K., Iida, M., Yanokura, M., Kisu, I., Iwata, T., Tominaga, E., Tanaka, K., & Aoki, D. (2014) · The Scientific World JOURNAL · doi:10.1155/2014/178075 · Cited by 147
Liu, T., Yuan, X., & Xu, D. (2016) · Genes · doi:10.3390/genes7070038 · Cited by 145
Human papillomavirus E6 and E7 oncoproteins as risk factors for tumorigenesis
Ganguly, N., & Parihar, S. P. (2009) · Journal of Biosciences · doi:10.1007/s12038-009-0013-7 · Cited by 138
Basukala, O., & Banks, L. (2021) · Viruses · doi:10.3390/v13101892 · Cited by 137
Molecular Mechanisms of Human Papillomavirus-Induced Carcinogenesis
Lehoux, M., D’Abramo, C. M., & Archambault, J. (2009) · Public Health Genomics · doi:10.1159/000214918 · Cited by 137
HPV E6, E6AP and cervical cancer
Beaudenon, S. L., & Huibregtse, J. M. (2008) · BMC Biochemistry · doi:10.1186/1471-2091-9-s1-s4 · Cited by 135
Genomic instability and cancer: Lessons learned from human papillomaviruses
Korzeniewski, N., Spardy, N. A., Duensing, A. U., & Duensing, S. M. (2010) · Cancer Letters · doi:10.1016/j.canlet.2010.10.013 · Cited by 118
Kelley, M. L., Keiger, K., Lee, C. J., & Huibregtse, J. M. (2005) · Journal of Virology · doi:10.1128/jvi.79.6.3737-3747.2005 · Cited by 110
The role of telomeres in the ageing of human skin: Telomeres and skin ageing
Buckingham, E. M., & Klingelhutz, A. J. (2011) · Experimental Dermatology · doi:10.1111/j.1600-0625.2010.01242.x · Cited by 109
Regulation of Telomerase and Telomeres: Human Tumor Viruses Take Control
Bellon, M., & Nicot, C. (2008) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djm269 · Cited by 106
Regulation of the Wnt/β-Catenin Signaling Pathway by Human Papillomavirus E6 and E7 Oncoproteins
Muñoz-Bello, J. O., Olmedo‐Nieva, L., Contreras‐Paredes, A., Gonzalez, A., Rocha‐Zavaleta, L., & Lizano, M. (2015) · Viruses · doi:10.3390/v7082842 · Cited by 101
Scheffner, M., & Staub, O. (2007) · BMC Biochemistry · doi:10.1186/1471-2091-8-s1-s6 · Cited by 100
HPV and head and neck cancers: Towards early diagnosis and prevention
Galati, L., Chiocca, S., Duca, D., Tagliabue, M., Simoens, C., Gheit, T., Arbyn, M., & Tommasino, M. (2022) · Tumour Virus Research · doi:10.1016/j.tvr.2022.200245 · Cited by 93
RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis
Gupta, S. M., & Mania‐Pramanik, J. (2019) · Journal of Biomedical Science · doi:10.1186/s12929-019-0520-2 · Cited by 92
RetractedLiu, X., Roberts, J., Dakic, A., Zhang, Y., & Schlegel, R. (2008) · Virology · doi:10.1016/j.virol.2008.02.025 · Cited by 90
The Drivers, Mechanisms, and Consequences of Genome Instability in HPV-Driven Cancers
Porter, V., & Marra, M. A. (2022) · Cancers · doi:10.3390/cancers14194623 · Cited by 88
Katzenellenbogen, R. A., Egelkrout, E. M., Vliet-Gregg, P., Gewin, L. C., Gafken, P. R., & Galloway, D. A. (2007) · Journal of Virology · doi:10.1128/jvi.02007-06 · Cited by 78
Self-citationBedard, K., Underbrink, M. P., Howie, H. L., & Galloway, D. A. (2008) · Journal of Virology · doi:10.1128/jvi.01818-07 · Cited by 88
Self-citationTerai, M., Uyama, T., Sugiki, T., Li, X., Umezawa, A., & Kiyono, T. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-07-0652 · Cited by 84
Self-citationEgawa, N. (2023) · International Journal of Clinical Oncology · doi:10.1007/s10147-023-02340-y · Cited by 82
Telomere-related Markers for Cancer
Yuan, X., Dai, M., & Xu, D. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200106145340 · Cited by 80
James, M. A., Lee, J. H., & Klingelhutz, A. J. (2006) · International Journal of Cancer · doi:10.1002/ijc.22064 · Cited by 64
Association between hTERT activation by HPV E6 proteins and oncogenic risk
Doorslaer, K. V., & Burk, R. D. (2012) · Virology · doi:10.1016/j.virol.2012.08.006 · Cited by 77
Jabbar, S. F., Strati, K., Shin, M. K., Pitot, H. C., & Lambert, P. F. (2010) · Virology · doi:10.1016/j.virol.2010.08.003 · Cited by 74
NFX1 Interacts with mSin3A/Histone Deacetylase To Repress hTERT Transcription in Keratinocytes
Xu, M., Luo, W., Elzi, D. J., Grandori, C., & Galloway, D. A. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01969-07 · Cited by 68
Self-citationBaleja, J., Cherry, J. J., Liu, Z., Gao, H., Nicklaus, M. C., Voigt, J. H., Chen, J. J., & Androphy, E. J. (2006) · Antiviral Research · doi:10.1016/j.antiviral.2006.03.014 · Cited by 73
E6AP-Dependent Degradation of DLG4/PSD95 by High-Risk Human Papillomavirus Type 18 E6 Protein
Handa, K., Yugawa, T., Narisawa‐Saito, M., Ohno, S.-I., Fujita, M., & Kiyono, T. (2006) · Journal of Virology · doi:10.1128/jvi.01712-06 · Cited by 73
Self-citationNovel Functions of the Human Papillomavirus E6 Oncoproteins
Wallace, N. A., & Galloway, D. A. (2015) · Annual Review of Virology · doi:10.1146/annurev-virology-100114-055021 · Cited by 70
Self-citationThe AtNFXL1 gene encodes a NF‐X1 type zinc finger protein required for growth under salt stress
Lisso, J., Altmann, T., & Müssig, C. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.07.079 · Cited by 70
Gabet, A., Accardi, R., Bellopede, A., Popp, S., Boukamp, P., Sylla, B. S., Londoño‐Vallejo, A., & Tommasino, M. (2007) · The FASEB Journal · doi:10.1096/fj.07-8389com · Cited by 70
HPV16 E6 augments Wnt signaling in an E6AP-dependent manner
Lichtig, H., Gilboa, D. A., Jackman, A., Gonen, P., Levav-Cohen, Y., Haupt, Y., & Sherman, L. (2010) · Virology · doi:10.1016/j.virol.2009.10.011 · Cited by 61
Liu, X., Dakic, A., Chen, R., Disbrow, G. L., Zhang, Y., Dai, Y., & Schlegel, R. (2008) · Journal of Virology · doi:10.1128/jvi.01318-08 · Cited by 68
hTERT promoter activity and CpG methylation in HPV-induced carcinogenesis
de Wilde, J., Kooter, J. M., Overmeer, R., Claassen-Kramer, D., Meijer, C. J. L. M., Snijders, P. J. F., & Steenbergen, R. D. M. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-271 · Cited by 67
Katzenellenbogen, R. A., Vliet-Gregg, P. A., Xu, M., & Galloway, D. A. (2009) · Journal of Virology · doi:10.1128/jvi.02556-08 · Cited by 67
Self-citationViral Mimicry to Usurp Ubiquitin and SUMO Host Pathways
Wimmer, P., & Schreiner, S. (2015) · Viruses · doi:10.3390/v7092849 · Cited by 66
Boscolo‐Rizzo, P., Mosto, M. C. D., Rampazzo, E., Giunco, S., Mistro, A. D., Menegaldo, A., Baboçi, L., Mantovani, M., Tirelli, G., & Rossi, A. D. (2016) · Cancer and Metastasis Reviews · doi:10.1007/s10555-016-9633-1 · Cited by 66
Sanduja, S., Kaza, V., & Dixon, D. A. (2009) · Aging · doi:10.18632/aging.100086 · Cited by 65
Human papillomavirus and molecular considerations for cancer risk
Whiteside, M. A., Siegel, E. M., & Unger, E. R. (2008) · Cancer · doi:10.1002/cncr.23750 · Cited by 65
Viruses – seeking and destroying the tumor program
O’Shea, C. C. (2005) · Oncogene · doi:10.1038/sj.onc.1209047 · Cited by 65
Manipulation of the ubiquitin–proteasome pathway by small DNA tumor viruses
Blanchette, P., & Branton, P. E. (2008) · Virology · doi:10.1016/j.virol.2008.10.005 · Cited by 64
Telomerase Induction in HPV Infection and Oncogenesis
Katzenellenbogen, R. A. (2017) · Viruses · doi:10.3390/v9070180 · Cited by 61
Galati, L., Chiantore, M. V., Marinaro, M., & Bonito, P. D. (2024) · Viruses · doi:10.3390/v16030416 · Cited by 59
Narisawa‐Saito, M., Handa, K., Yugawa, T., Ohno, S.-I., Fujita, M., & Kiyono, T. (2006) · Oncogene · doi:10.1038/sj.onc.1210118 · Cited by 58
Self-citationAsano, T., Masuda, D., Yasuda, M., Nakashita, H., Kudo, T., Kimura, M., Yamaguchi, K., & Nishiuchi, T. (2007) · The Plant Journal · doi:10.1111/j.1365-313x.2007.03353.x · Cited by 57
Human telomerase expression regulation
Machnik, M., Wojtyla, A., & Rubiś, B. (2011) · Biochemistry and Cell Biology · doi:10.1139/o11-037 · Cited by 56
Park, Y.-J., Kim, E. K., Bae, J. Y., Moon, S., & Kim, J. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.10.021 · Cited by 53
Telomerase as a useful target in cancer fighting—the breast cancer case
Hołysz, H., Lipińska, N., Paszel-Jaworska, A., & Rubiś, B. (2013) · Tumor Biology · doi:10.1007/s13277-013-0757-4 · Cited by 53
Identification of annexin A1 as a novel substrate for E6AP‐mediated ubiquitylation
Shimoji, T., Murakami, K., Sugiyama, Y., Matsuda, M., Inubushi, S., Nasu, J., Shirakura, M., Suzuki, T., Wakita, T., Kishino, T., et al. (2009) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22096 · Cited by 51
Annunziata, C., Pezzuto, F., Greggi, S., Ionna, F., Losito, S., Botti, G., Buonaguro, L., Buonaguro, F. M., & Tornesello, M. L. (2018) · International Journal of Cancer · doi:10.1002/ijc.31412 · Cited by 50
Genetic variations in human papillomavirus and cervical cancer outcomes
Rader, J. S., Tsaih, S., Fullin, D., Murray, M. W., Iden, M., Zimmermann, M. T., & Flister, M. J. (2018) · International Journal of Cancer · doi:10.1002/ijc.32038 · Cited by 50
The molecular pathogenesis of penile carcinoma—current developments and understanding
Emmanuel, A., Nettleton, J., Watkin, N. A., & Berney, D. M. (2019) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-019-02607-8 · Cited by 50
Chapter 2 An Evolutionary Perspective on Parasitism as a Cause of Cancer
Ewald, P. W. (2009) · Advances in Parasitology/Advances in parasitology · doi:10.1016/s0065-308x(08)00602-7 · Cited by 50
Kong, L.-J., Meloni, A. R., & Nevins, J. R. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.02.016 · Cited by 48
Zhang, Y., Dakic, A., Chen, R., Dai, Y., Schlegel, R., & Liu, X. (2017) · Oncotarget · doi:10.18632/oncotarget.22036 · Cited by 48
NFX1 Plays a Role in Human Papillomavirus Type 16 E6 Activation of NFκB Activity
Xu, M., Katzenellenbogen, R. A., Grandori, C., & Galloway, D. A. (2010) · Journal of Virology · doi:10.1128/jvi.00538-10 · Cited by 47
Self-citationTERT promoter hot spot mutations are frequent in Indian cervical and oral squamous cell carcinomas
Vinothkumar, V., Arunkumar, G., Revathidevi, S., Arun, K., Manikandan, M., Rao, A. K. D. M., Seenivasagam, R. K., Ajay, C., Rajaraman, R., Ramani, R., et al. (2015) · Tumor Biology · doi:10.1007/s13277-015-4694-2 · Cited by 47
Katzenellenbogen, R. A., Vliet-Gregg, P. A., Xu, M., & Galloway, D. A. (2010) · Journal of Virology · doi:10.1128/jvi.01377-10 · Cited by 46
Self-citationTornesello, M. L., Cerasuolo, A., Starita, N., Amiranda, S., Bonelli, P., Tuccillo, F. M., Buonaguro, F. M., Buonaguro, L., & Tornesello, A. L. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1286683 · Cited by 42
NFX1-123 and human papillomavirus 16E6 increase Notch expression in keratinocytes
Vliet-Gregg, P. A., Hamilton, J. R., & Katzenellenbogen, R. A. (2013) · Journal of Virology · doi:10.1128/jvi.02582-13 · Cited by 36
Binding of Human Papillomavirus Type 16 E6 to E6AP Is Not Required for Activation of hTERT
Šekaric, P., Cherry, J. J., & Androphy, E. J. (2007) · Journal of Virology · doi:10.1128/jvi.01776-07 · Cited by 42
Sitaram, R. T., Degerman, S., Ljungberg, B., Andersson, E., Oji, Y., Sugiyama, H., Roos, G., & Li, A. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605878 · Cited by 41
Wanichwatanadecha, P., Sirisrimangkorn, S., Kaewprag, J., & Ponglikitmongkol, M. (2012) · Journal of General Virology · doi:10.1099/vir.0.038265-0 · Cited by 41
Telomeres and Telomerase During Human Papillomavirus-Induced Carcinogenesis
Pańczyszyn, A., Boniewska‐Bernacka, E., & Głąb, G. (2018) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-018-0336-x · Cited by 40
The Hallmarks of Cervical Cancer: Molecular Mechanisms Induced by Human Papillomavirus
Chalma, P. R., Antonio-Véjar, V., Tejedor, J. G. O., Ortíz, J., Vega, B., & Ordóñez, G. D. B. (2024) · Biology · doi:10.3390/biology13020077 · Cited by 39
Infection, mutation, and cancer evolution
Ewald, P. W., & Ewald, H. A. S. (2012) · Journal of Molecular Medicine · doi:10.1007/s00109-012-0891-2 · Cited by 39
Metadata
- Authors
- Gewin, L., Myers, H., Kiyono, T., & Galloway, D. A.
- Affiliations
- University of Washington (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2004-09-15
- Volume
- 18
- Issue
- 18
- Pages
- 2269-2282
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC517520
- OpenAlex
- W2127352755
- Cited by
- 277
- References
- 60
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 8 · 2023: 8 · 2022: 10 · 2021: 10 · 2020: 14 · 2019: 12 · 2018: 14 · 2017: 11 · 2016: 13 · 2015: 13 · 2014: 13 · 2013: 11 · 2012: 17
- Type
- posted content
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- National Cancer Institute (T32CA009229, 5 T32 CA 09229-23, R01CA064795)
- National Institute of Allergy and Infectious Diseases (T32AI007140)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- HPV16, E6 oncoprotein, UBE3A, E3 ubiquitin ligase, hTERT promoter, ubiquitination, p53 degradation, epithelial cells
- MeSH terms
- Amino Acid Sequence, Binding Sites, Cells, Cultured, DNA-Binding Proteins, Enzyme Activation, Humans, Molecular Sequence Data, Mutation, Oncogene Proteins, Viral, Promoter Regions, Genetic, Repressor Proteins, Tumor Suppressor Protein p53, Genes, myc, Telomerase, Protein Isoforms, Ubiquitin-Protein Ligases, Macromolecular Substances
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-12, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-12 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
