c-Myc Is Glycosylated at Threonine 58, a Known Phosphorylation Site and a Mutational Hot Spot in Lymphomas
Open accessAbstract
c-Myc is a helix-loop leucine zipper phosphoprotein that heterodimerizes with Max and regulates gene transcription in cell proliferation, cell differentiation, and programmed cell death. Previously, we demonstrated that c-Myc is modified by O-linked N-acetylglucosamine (O-GlcNAc) within or nearby the N-terminal transcriptional activation domain (Chou, T.-Y., Dang, C.V., and Hart, G.W. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 4417-4421). In this paper, we identified the O-GlcNAc attachment site(s) on c-Myc. c-Myc purified from sf9 insect cells was trypsinized, and its GlcNAc moieties were enzymically labeled with [3H]galactose. The [3H]galactose-labeled glycopeptides were isolated by reverse phase high performance liquid chromatography and then subjected to gas-phase sequencing, manual Edman degradation, and laser desorption/ionization mass spectrometry. These analyses show that threonine 58, an in vivo phosphorylation site in the transactivation domain, is the major O-GlcNAc glycosylation site of c-Myc. Mutation of threonine 58, frequently found in retroviral v-Myc proteins and in human Burkitt and AIDS-related lymphomas, is associated with enhanced transforming activity and tumorigenicity. The reciprocal glycosylation and phosphorylation at this biologically significant amino acid residue may play an important role in the regulation of the functions of c-Myc.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Induction of apoptosis in fibroblasts by c-myc protein
Evan, G. I., Wyllie, A. H., Gilbert, C. S., Littlewood, T. D., Land, H., Brooks, M. W., Waters, C. M., Penn, L. Z., & Hancock, D. C. (1992) · Cell · doi:10.1016/0092-8674(92)90123-t · Cited by 2,941 · see citing works
Max: A Helix-Loop-Helix Zipper Protein That Forms a Sequence-Specific DNA-Binding Complex with Myc
Blackwood, E. M., & Eisenman, R. N. (1991) · Science · doi:10.1126/science.2006410 · Cited by 1,681 · see citing works
A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures.
Summers, & Smith, G. (1987) · Cited by 1,679 · see citing works
Sequence-Specific DNA Binding by the c-Myc Protein
Blackwell, T. K., Kretzner, L., Blackwood, E. M., Eisenman, R. N., & Weintraub, H. M. (1990) · Science · doi:10.1126/science.2251503 · Cited by 863 · see citing works
Holt, G. D., & Hart, G. W. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)57510-x · Cited by 498 · see citing works
Self-citationDefinition of regions in human c-myc that are involved in transformation and nuclear localization.
Stone, J. C., de Lange, T., Ramsay, G. M., Jakobovits, E. B., Bishop, J. M., VARMUS, H. E., & Lee, W. (1987) · Molecular and Cellular Biology · doi:10.1128/mcb.7.5.1697 · Cited by 446 · see citing works
An Amino-Terminal c-Myc Domain Required for Neoplastic Transformation Activates Transcription
Kato, G. J., Barrett, J., Villa‐Garcia, M., & Dang, C. V. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.11.5914 · Cited by 407 · see citing works
Self-citationRNA polymerase II is a glycoprotein. Modification of the COOH-terminal domain by O-GlcNAc
Kelly, W. G., Dahmus, M. E., & Hart, G. W. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82216-5 · Cited by 399 · see citing works
Self-citationGLYCOSYLATION IN THE NUCLEUS AND CYTOPLASM
Hart, G. W., Haltiwanger, R. S., Holt, G. D., & Kelly, W. G. (1989) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.58.070189.004205 · Cited by 386 · see citing works
Self-citationNonenzymatic glycosylation of albumin in vivo. Identification of multiple glycosylated sites.
Iberg, N., & Flückiger, R. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)67052-8 · Cited by 380 · see citing works
c-myc oncogene protein synthesis is independent of the cell cycle in human and avian cells
Hann, S., Thompson, C. B., & Eisenman, R. N. (1985) · Nature · doi:10.1038/314366a0 · Cited by 369 · see citing works
Bhatia, K., Huppi, K. E., Spangler, G., Siwarski, D. F., Iyer, R., & Magrath, I. T. (1993) · Nature Genetics · doi:10.1038/ng0993-56 · Cited by 285 · see citing works
Altered nucleotide sequences of a translocated c-myc gene in Burkitt lymphoma
Rabbitts, T. H., Hamlyn, P. H., & Baer, R. J. (1983) · Nature · doi:10.1038/306760a0 · Cited by 285 · see citing works
Myc oncoproteins are phosphorylated by casein kinase II.
Lüscher, B., Kuenzel, E. A., Krebs, E. G., & Eisenman, R. N. (1989) · The EMBO Journal · doi:10.1002/j.1460-2075.1989.tb03481.x · Cited by 272 · see citing works
Factors affecting retention and resolution of peptides in high-performance liquid chromatography
Meek, J. L., & Rossetti, Z. L. (1981) · Journal of Chromatography A · doi:10.1016/s0021-9673(00)81169-3 · Cited by 250 · see citing works
Site-specific modulation of c-Myc cotransformation by residues phosphorylated in vivo.
Pulverer, B., Fisher, C., Vousden, K. H., Littlewood, T. D., Evan, G. I., & Woodgett, J. R. (1994) · PubMed · Cited by 228 · see citing works
Glycosylation of the c-Myc transactivation domain.
Chou, T., Dang, C. V., & Hart, G. W. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.10.4417 · Cited by 225 · see citing works
Self-citationSeth, A., Alvarez, E., Gupta, S., & Davis, R. J. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)54312-x · Cited by 222 · see citing works
Lutterbach, B. A., & Hann, S. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.8.5510 · Cited by 220 · see citing works
Function of the c‐Myc oncoprotein
Kato, G. J., & Dang, C. V. (1992) · The FASEB Journal · doi:10.1096/fasebj.6.12.1521738 · Cited by 167 · see citing works
Self-citationPhosphorylation sites mapping in the N-terminal domain of c-myc modulate its transforming potential.
Henriksson, M., Bakardjiev, A. I., Klein, G., & Lüscher, B. (1993) · PubMed · Cited by 162 · see citing works
Production of human c-myc protein in insect cells infected with a baculovirus expression vector.
Miyamoto, C., Smith, G., Farrell-Towt, J., et al. (1985) · Molecular and Cellular Biology · doi:10.1128/mcb.5.10.2860 · Cited by 143 · see citing works
[26] Detection of O-Linked N-acetylglucosamine (O-GlcNAc) on cytoplasmic and nuclear proteins
Roquemore, E. P., Chou, T., & Hart, G. W. (1994) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(94)30028-3 · Cited by 136 · see citing works
Self-citationDefinition of the activities and properties of c-myc required to inhibit cell differentiation.
Freytag, S. O., Dang, C. V., & Lee, W. M. (1990) · PubMed · Cited by 103 · see citing works
Self-citationClustered mutations in the second exon of the MYC gene in sporadic Burkitt's lymphoma.
Yano, T., Sander, C. A., Clark, H. M., Dolezal, M. V., Jaffe, E. S., & Raffeld, M. A. (1993) · PubMed · Cited by 101 · see citing works
Bhatia, K. G., Spangler, G., Gaïdano, G., Hamdy, N., Dalla‐Favera, R., & Magrath, I. T. (1994) · Blood · doi:10.1182/blood.v84.3.883.883 · Cited by 88 · see citing works
A manual sequencing method for identification of phosphorylated amino acids in phosphopeptides
Sullivan, S., & Wong, T. W. (1991) · Analytical Biochemistry · doi:10.1016/0003-2697(91)90356-x · Cited by 87 · see citing works
Palmieri, S., Kahn, P., & Graf, T. (1983) · The EMBO Journal · doi:10.1002/j.1460-2075.1983.tb01750.x · Cited by 83 · see citing works
Greis, K. D., Gibson, W., & Hart, G. W. (1994) · Journal of Virology · doi:10.1128/jvi.68.12.8339-8349.1994 · Cited by 78 · see citing works
Self-citationJp, M., Dc, H., Littlewood, T. D., & Evan, G. I. (1987) · PubMed · Cited by 76 · see citing works
Mutations in the coding region of c-MYC in AIDS-associated and other aggressive lymphomas.
Clark, H. M., Yano, T., Otsuki, T., et al. (1994) · PubMed · Cited by 72 · see citing works
Albert, T., Urlbauer, B., Kohlhuber, F., Hammersen, B., & Eick, D. (1994) · PubMed · Cited by 66 · see citing works
Sequence curiosity in v-myc oncogene
Papas, T. S., & Lautenberger, J. A. (1985) · Nature · doi:10.1038/318237a0 · Cited by 54 · see citing works
Expression, Glycosylation, and Phosphorylation of Human Keratins 8 and 18 in Insect Cells
Ku, N., & Omary, M. B. (1994) · Experimental Cell Research · doi:10.1006/excr.1994.1054 · Cited by 51 · see citing works
DNA binding activities of c-Myc purified from eukaryotic cells.
Papoulas, O., Williams, N. G., & Kingston, R. E. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)50042-4 · Cited by 49 · see citing works
The transforming activity of the chicken c-myc gene can be potentiated by mutations.
Frykberg, L., Graf, T., & Vennström, B. (1987) · PubMed · Cited by 44 · see citing works
Symonds, G. P., Hartshorn, A., Kennewell, A., et al. (1989) · PubMed · Cited by 37 · see citing works
Chevrier, M. R., Cotter, R. J., & Roepstorff, P. (1991) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.1290051209 · Cited by 33 · see citing works
Raffeld, M. A., Yano, T., Hoang, A. T., Lewis, B., Clark, H. M., Otsuki, T., & Dang, C. V. (1995) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-79275-5_31 · Cited by 21 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- Chou, T.-Y., Dang, C. V., and Hart, G. W. (1995) Proc. Natl. Acad. Sci. U. S. A. 92,4417-4421
- Hart, G. W., Kelly, W. G., Blomberg, M. A., Roquemore, E. P., Dong, L.-Y. D., Kreppel, L., Chou, T.-Y., Snow, D., and Greis, K. (1993) in 44. Colloquium Mosbach 1993 Glyco-and Cell Biology, pp. 91-103, Springer-Verlag, Berlin
Cited by
Sorted by citations
Varki, A. (2017) · Glycobiology · doi:10.1093/glycob/cww086 · Cited by 2,635 · see citing works
“The discovery of O-linked GlcNAc (310-314) thus went unrecognized even by most other glycoscientists for years, until it was finally realized that this nucleocytoplasmic modification is the most common form of glycosylation in eukaryotic cells (314) (315) (316) , and that it mediates numerous modulatory functions on m…”
BackgroundCycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins
Hart, G. W., Housley, M. P., & Slawson, C. (2007) · Nature · doi:10.1038/nature05815 · Cited by 1,418 · see citing works
Self-citationHart, G. W., Slawson, C., Ramirez-Correa, G., & Lagerlof, O. (2011) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060608-102511 · Cited by 1,317 · see citing works
Self-citationA potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo
Yuzwa, S. A., Macauley, M. S., Heinonen, J. E., Shan, X., Dennis, R. J., He, Y., Whitworth, G. E., Stubbs, K. A., McEachern, E. J., Davies, G. J., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.96 · Cited by 717 · see citing works
Cellular Metabolic Stress: Considering How Cells Respond to Nutrient Excess
Wellen, K. E., & Thompson, C. B. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.10.004 · Cited by 486 · see citing works
Regulation of cancer cell metabolism: Oncogenic MYC in the driver’s seat
Dong, Y., Tu, R., Liu, H., & Qing, G. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00235-2 · Cited by 405 · see citing works
Cell signaling, the essential role of O-GlcNAc
Zachara, N. E., & Hart, G. W. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2006.04.007 · Cited by 386 · see citing works
The Microtubule-associated Protein Tau Is Extensively Modified with O-linked N-acetylglucosamine
Arnold, C. S., Johnson, G. W., Cole, R. N., Dong, D. L.-Y., Lee, M., & Hart, G. W. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.46.28741 · Cited by 361 · see citing works
Self-citationO-GlcNAc signaling: a metabolic link between diabetes and cancer?
Slawson, C., Copeland, R. J., & Hart, G. W. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.04.005 · Cited by 346 · see citing works
Self-citationGlycan-dependent signaling: O-linked N-acetylglucosamine
HANOVER, J. A. (2001) · The FASEB Journal · doi:10.1096/fj.01-0094rev · Cited by 283 · see citing works
The Emerging Link between O-GlcNAc and Alzheimer Disease
Zhu, Y., Shan, X., Yuzwa, S. A., & Vocadlo, D. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.601351 · Cited by 267 · see citing works
O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis
Taparra, K., Wang, H., Malek, R., Lafargue, A., Barbhuiya, M. A., Wang, X., Simons, B. W., Ballew, M., Nugent, K., Groves, J., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci94844 · Cited by 80 · see citing works
Barfeld, S. J., East, P., Zuber, V., & Mills, I. G. (2014) · BMC Medical Genomics · doi:10.1186/s12920-014-0074-9 · Cited by 47 · see citing works
Frank, L. A., Sutton‐McDowall, M. L., Gilchrist, R. B., & Thompson, J. G. (2014) · Molecular Reproduction and Development · doi:10.1002/mrd.22299 · Cited by 18 · see citing works
Williams, E. T., Schiefelbein, K., Schuster, M., Ahmed, I. M. M., De Vries, M., Beveridge, R., Zerbe, O., & Hartrampf, N. (2024) · Chemical Science · doi:10.1039/d4sc00481g · Cited by 13 · see citing works
- Authors
- Chou, T.-Y., Hart, G. W., & Dang, C. V.
- Affiliations
- Johns Hopkins University (US)
- University of Alabama at Birmingham (US)
- Corresponding author
- Hart, Gerald W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-08
- Volume
- 270
- Issue
- 32
- Pages
- 18961-18965
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2060799932
- Cited by
- 453
- References
- 39
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 13 · 2023: 24 · 2022: 11 · 2021: 18 · 2020: 10 · 2019: 9 · 2018: 18 · 2017: 20 · 2016: 20 · 2015: 13 · 2014: 21 · 2013: 19 · 2012: 14
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA 57341, R01CA057341, CA-42486, R01CA042486)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Keywords
- c-Myc, O-GlcNAcylation, protein phosphorylation, transactivation domain, lymphoma, Burkitt lymphoma, HIV-associated lymphoma, transforming activity, tumorigenicity
- MeSH terms
- Amino Acid Sequence, Animals, Glycosylation, Lymphoma, Molecular Sequence Data, Mutation, Phosphorylation, Recombinant Proteins, Threonine, Proto-Oncogene Proteins c-myc, Spodoptera
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
