Cited by 879Cancer-related Molecular PathwaysCervical Cancer and HPV ResearchUbiquitin and proteasome pathways

The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.

A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18.

Open access

Huibregtse, J.M., Scheffner, M., Howley, P.M.·1991·The EMBO Journal

DOI 10.1002/j.1460-2075.1991.tb04990.xPMC PMC453163

Open this paper in CoChat — free account

Abstract

The E6 protein of human papillomavirus types 16 and 18 (HPV-16 and HPV-18) can stably associate with the p53 protein in vitro. In the presence of rabbit reticulocyte lysate, this association leads to the specific degradation of p53 through the ubiquitin-dependent proteolysis system. We have examined the E6-p53 complex in more detail and have found that association of E6 with p53 is mediated by an additional cellular factor. This factor is present in rabbit reticulocyte lysate, primary human keratinocytes and in each of five human cell lines examined. The factor is designated E6-AP, for E6-associated protein, based on the observation that the E6 proteins of HPV-16 and 18 can form a stable complex with the factor in the absence of p53, whereas p53 association with the factor can be detected only in the presence of E6. Gel filtration and coprecipitation experiments indicate that E6-AP is a monomeric protein of approximately 100 kDa.

Integrity signals

Registry

Crossref · 10.1002/j.1460-2075.1991.tb04990.x

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

The text we found for this paper looks like another document, so its claims and self-check weren’t run. The registry and citation checks still apply.

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The text we found for this paper looks like another document, so the self-check wasn’t run.

Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase
Smith, D. B., & Johnson, K. S. (1988) · Gene · doi:10.1016/0378-1119(88)90005-4 · Cited by 5,844
The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53
Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J., & Howley, P. M. (1990) · Cell · doi:10.1016/0092-8674(90)90409-8 · Cited by 3,995
Self-citation
The human papilloma virus-16 E7-oncoprotein is able to bind to the retinoblastoma gene product
Dyson, N., Howley, P. M., Münger, K., & Harlow, E. (1989) · Science · doi:10.1126/science.2537532 · Cited by 3,017
Self-citation
Association of Human Papillomavirus Types 16 and 18 E6 Proteins with p53
Werness, B. A., Levine, A. J., & Howley, P. M. (1990) · Science · doi:10.1126/science.2157286 · Cited by 2,562
Self-citation
T antigen is bound to a host protein in SY40-transformed cells
Lane, D. P., & Crawford, L. V. (1979) · Nature · doi:10.1038/278261a0 · Cited by 2,456
Cyclin is degraded by the ubiquitin pathway
Glotzer, M., Murray, A. W., & Kirschner, M. W. (1991) · Nature · doi:10.1038/349132a0 · Cited by 2,359
Characterization of a 54K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells
Linzer, D. I. H., & Levine, A. J. (1979) · Cell · doi:10.1016/0092-8674(79)90293-9 · Cited by 1,814
Structure and transcription of human papillomavirus sequences in cervical carcinoma cells
Schwarz, E., Freese, U. K., Gissmann, L., Mayer, W., Roggenbuck, B., Stremlau, A., & Hausen, H. Z. (1985) · Nature · doi:10.1038/314111a0 · Cited by 1,483
SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene
DeCaprio, J. A., Ludlow, J. W., Figge, J., Shew, J.-Y., Huang, C.-M., Lee, W.-H., Marsilio, E., Paucha, E., & Livingston, D. M. (1988) · Cell · doi:10.1016/0092-8674(88)90559-4 · Cited by 1,459
Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product
Whyte, P., Buchkovich, K. J., Horowitz, J. M., Friend, S. H., Raybuck, M., Weinberg, R. A., & Harlow, E. (1988) · Nature · doi:10.1038/334124a0 · Cited by 1,403
The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes
Münger, K., Phelps, W. C., Bubb, V. J., Howley, P. M., & Schlegel, R. (1989) · Journal of Virology · doi:10.1128/jvi.63.10.4417-4421.1989 · Cited by 1,335
Self-citation
Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product.
Münger, K., Werness, B. A., Dyson, N. J., Phelps, W. C., Harlow, E. E., & Howley, P. M. (1989) · The EMBO Journal · doi:10.1002/j.1460-2075.1989.tb08594.x · Cited by 1,204
Self-citation
Identification of p53 as a Sequence-Specific DNA-Binding Protein
Kern, S. E., Kinzler, K. W., Bruskin, A. M., Jarosz, D., Friedman, P. N., Prives, C. L., & Vogelstein, B. (1991) · Science · doi:10.1126/science.2047879 · Cited by 1,085
HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes.
Hawley‐Nelson, P., Vousden, K. H., Hubbert, N. L., Lowy, D. R., & Schiller, J. T. (1989) · The EMBO Journal · doi:10.1002/j.1460-2075.1989.tb08570.x · Cited by 914
The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines.
Scheffner, M., Münger, K., Byrne, J. C., & Howley, P. M. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.13.5523 · Cited by 850
Self-citation
Adenovirus E1b-58kd tumor antigen and SV40 large tumor antigen are physically associated with the same 54 kd cellular protein in transformed cells
Sarnow, P., Ho, Y.-S., Williams, J., & Levine, A. J. (1982) · Cell · doi:10.1016/0092-8674(82)90356-7 · Cited by 836
Presence of a Potent Transcription Activating Sequence in the p53 Protein
Fields, S., & Jang, S. K. (1990) · Science · doi:10.1126/science.2144363 · Cited by 790
p53 Functions as a Cell Cycle Control Protein in Osteosarcomas
Diller, L., Kassel, J., Nelson, C. E., Gryka, M. A., Litwak, G., Gebhardt, M. C., Bressac, B., Öztürk, M., Baker, S. J., Vogelstein, B., et al. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.11.5772 · Cited by 775
Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis.
Hershko, A., Ciechanover, A. J., Heller, H., Haas, A. L., & Rose, I. A. (1980) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.77.4.1783 · Cited by 769
Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines
Baker, C. C., Phelps, W. C., Lindgren, V., Braun, M. J., Gonda, M. A., & Howley, P. M. (1987) · Journal of Virology · doi:10.1128/jvi.61.4.962-971.1987 · Cited by 757
Self-citation
Transcription of human papillomavirus type 16 early genes in a cervical cancer and a cancer-derived cell line and identification of the E7 protein.
Smotkin, D., & Wettstein, F. O. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.13.4680 · Cited by 661
A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes
Ciehanover, A., Hod, Y., & Hershko, A. (1978) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(78)91249-4 · Cited by 649
Transcriptional Activation by Wild-Type but Not Transforming Mutants of the p53 Anti-Oncogene
Raycroft, L., Wu, H., & Lozano, G. (1990) · Science · doi:10.1126/science.2144364 · Cited by 620
TGF-β1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains
Pietenpol, J. A., Stein, R. W., Morán, E., Yaciuk, P., Schlegel, R., Lyons, R. M., Pittelkow, M. R., Münger, K., Howley, P. M., & Moses, H. L. (1990) · Cell · doi:10.1016/0092-8674(90)90188-k · Cited by 597
Self-citation
Transformation of human fibroblasts and keratinocytes with human papillomavirus type 16 DNA
Pirisi, L. A., Yasumoto, S., Feller, M. J., Doniger, J., & DiPaolo, J. A. (1987) · Journal of Virology · doi:10.1128/jvi.61.4.1061-1066.1987 · Cited by 528
Cellular localization and cell cycle regulation by a temperature-sensitive p53 protein.Preprint
Martinez, J., Georgoff, I., Martinez, J., & Levine, A. J. (1991) · Genes & Development · doi:10.1101/gad.5.2.151 · Cited by 528
Mutations in the p53 gene are frequent in primary, resected non-small cell lung cancer. Lung Cancer Study Group.
Chiba, I., Takahashi, T., Nau, M. M., D'Amico, D., Dt, C., Mitsudomi, T., Buchhagen, D. L., Carbone, D. P., Piantadosi, S., & KOGA, H. (1990) · PubMed · Cited by 514
Post-translational regulation of the 54K cellular tumor antigen in normal and transformed cells.
Oren, M., Maltzman, W., & Levine, A. J. (1981) · Molecular and Cellular Biology · doi:10.1128/mcb.1.2.101 · Cited by 489
Rearrangement of the p53 gene in human osteogenic sarcomas.
Masuda, H., Miller, C., Koeffler, H. P., Battifora, H. A., & Cline, M. J. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.21.7716 · Cited by 473
Ubiquitin-mediated protein degradation.
Hershko, A. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)37575-1 · Cited by 447
The Yeast Cell Cycle Gene CDC34 Encodes a Ubiquitin-Conjugating Enzyme
Goebl, M. G., Yochem, J., Jentsch, S., McGrath, J. P., Varshavsky, A. J., & Byers, B. (1988) · Science · doi:10.1126/science.2842867 · Cited by 420
Molecular and cytogenetic analysis of immortalized human primary keratinocytes obtained after transfection with human papillomavirus type 16 DNA.
Dürst, M., Dzarlieva, R., Boukamp, P., Fusenig, N. E., & Gissmann, L. (1987) · PubMed · Cited by 412
ATP-dependent incorporation of 20S protease into the 26S complex that degrades proteins conjugated to ubiquitin.
Eytan, E., Ganoth, D., Armon, T., & Hershko, A. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.20.7751 · Cited by 367
Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication
Bargonetti, J., Friedman, P. N., Kern, S. E., Vogelstein, B., & Prives, C. L. (1991) · Cell · doi:10.1016/0092-8674(91)90560-l · Cited by 367
Degradation of nuclear oncoproteins by the ubiquitin system in vitro.
Ciechanover, A. J., DiGiuseppe, J. A., Bercovich, B., Orian, A., Richter, J. D., Schwartz, A. L., & Brodeur, G. M. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.1.139 · Cited by 336
Two distinct mechanisms regulate the levels of a cellular tumor antigen, p53.
Reich, N. C., Oren, M., & Levine, A. J. (1983) · Molecular and Cellular Biology · doi:10.1128/mcb.3.12.2143 · Cited by 310
p53 and DNA polymerase α compete for binding to SV40 T antigen
Gannon, J., & Lane, D. P. (1987) · Nature · doi:10.1038/329456a0 · Cited by 278
Association between poor prognosis in early-stage invasive cervical carcinomas and non-detection of HPV DNA
RIOU, P. (1990) · The Lancet · doi:10.1016/0140-6736(90)92693-c · Cited by 273
p53 point mutation in HPV negative human cervical carcinoma cell lines.
Crook, T., Wrede, C. D., & Vousden, K. H. (1991) · PubMed · Cited by 272
Quantitative keratinocyte assay detects two biological activities of human papillomavirus DNA and identifies viral types associated with cervical carcinoma.
Schlegel, R., Phelps, W. C., Zhang, Y., & Barbosa, M. S. (1988) · The EMBO Journal · doi:10.1002/j.1460-2075.1988.tb03185.x · Cited by 258
p53 Functions as a Cell Cycle Control Protein in Osteosarcomas
Diller, L., Kassel, J., Nelson, C. E., et al. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.11.5772-5781.1990 · Cited by 228
The murine p53 protein blocks replication of SV40 DNA in vitro by inhibiting the initiation functions of SV40 large T antigen
Wang, E. H., Friedman, P. N., & Prives, C. L. (1989) · Cell · doi:10.1016/0092-8674(89)90913-6 · Cited by 215
Mouse p53 inhibits SV40 origin-dependent DNA replication
Braithwaite, A. W., Stürzbecher, H.-W., Addison, C. M., Palmer, C., Rudge, K., & Jenkins, J. R. (1987) · Nature · doi:10.1038/329458a0 · Cited by 206
Characterization of primary human keratinocytes transformed by human papillomavirus type 18
Kaur, P., & McDougall, J. K. (1988) · Journal of Virology · doi:10.1128/jvi.62.6.1917-1924.1988 · Cited by 193
Post-Translational Regulation of the 54K Cellular Tumor Antigen in Normal and Transformed Cells
Oren, M., Maltzman, W., & Levine, A. J. (1981) · Molecular and Cellular Biology · doi:10.1128/mcb.1.2.101-110.1981 · Cited by 181
Cis-trans recognition and subunit-specific degradation of short-lived proteins
Johnson, E. S., Gonda, D. K., & Varshavsky, A. J. (1990) · Nature · doi:10.1038/346287a0 · Cited by 153
How are substrates recognized by the ubiquitin-mediated proteolytic system
Ciechanover, A. J., & Schwartz, A. L. (1989) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(89)90180-1 · Cited by 125
Two Distinct Mechanisms Regulate the Levels of a Cellular Tumor Antigen, p53
Reich, N. C., Oren, M., & Levine, A. J. (1983) · Molecular and Cellular Biology · doi:10.1128/mcb.3.12.2143-2150.1983 · Cited by 106
Expression of RB and p53 proteins in HPV‐positive and HPV‐negative cervical carcinoma cell lines
Wrede, C. D., TIDY, J. A., Crook, T., Lane, D. P., & Vousden, K. H. (1991) · Molecular Carcinogenesis · doi:10.1002/mc.2940040302 · Cited by 80

Sorted by citations

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 2,416
Self-citation
Human papillomavirus oncoproteins: pathways to transformation
Moody, C. A., & Laimins, L. A. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2886 · Cited by 1,814
UBIQUITIN-DEPENDENT PROTEIN DEGRADATION
Hochstrasser, M. (1996) · Annual Review of Genetics · doi:10.1146/annurev.genet.30.1.405 · Cited by 1,706
ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways
Zhang, Y., Xiong, Y., & Yarbrough, W. G. (1998) · Cell · doi:10.1016/s0092-8674(00)81401-4 · Cited by 1,626
Protein ubiquitination involving an E1–E2–E3 enzyme ubiquitin thioester cascade
Scheffner, M., Nuber, U. A., & Huibregtse, J. M. (1995) · Nature · doi:10.1038/373081a0 · Cited by 1,017
Self-citation

See all 879

Authors: Huibregtse, J. M., Scheffner, M., & Howley, P. M.
Affiliations: National Institutes of Health (US)
ORCID: Huibregtse, J.M.
Scheffner, M.
Howley, P.M.
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 1991-12-01
Volume: 10
Issue: 13
Pages: 4129-4135
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1002/j.1460-2075.1991.tb04990.x
PMC: PMC453163
OpenAlex: W140061535
Cited by: 879
References: 46
Citations by year: 2026: 8 · 2025: 15 · 2024: 16 · 2023: 26 · 2022: 21 · 2021: 25 · 2020: 27 · 2019: 18 · 2018: 28 · 2017: 29 · 2016: 19 · 2015: 26 · 2014: 29 · 2013: 28 · 2012: 41
FWCI: 5.96
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: The EMBO Journal (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft
National Cancer Institute
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: p53, E6 oncoprotein, HPV16, HPV 18, UBE3A, ubiquitin-mediated proteolysis, p53 degradation, protein-protein interaction, keratinocytes, tumor suppressor
MeSH terms: Animals, Cell Line, Chromatography, Gel, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, Humans, Hydrolysis, Oncogene Proteins, Viral, Plasmids, Protein Binding, Proteins, Repressor Proteins, Reticulocytes, Tumor Suppressor Protein p53, Papillomaviridae

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.

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

A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18.

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks