Glycogen synthase kinase 3-dependent phosphorylation of Mdm2 regulates p53 abundance
Open accessAbstract
The Mdm2 oncoprotein regulates abundance and activity of the p53 tumor suppressor protein. For efficient degradation of p53, Mdm2 needs to be phosphorylated at several contiguous residues within the central conserved domain. We show that glycogen synthase kinase 3 (GSK-3) phosphorylated the Mdm2 protein in vitro and in vivo in the central domain. Inhibition of GSK-3 rescued p53 from degradation in an Mdm2-dependent manner while its association with Mdm2 was not affected. Likewise, inhibition of GSK-3 did not alter localization of p53 and Mdm2 or the interaction of Mdm2 and MdmX. Ionizing radiation, which leads to p53 accumulation, directed phosphorylation of GSK-3 at serine 9, which preceded and overlapped with the increase in p53 levels. Moreover, expression of a GSK-3 mutant where serine 9 was replaced with an alanine reduced the accumulation of p53 and induction of its target p21(WAF-1). We therefore conclude that inhibition of GSK-3 contributes to hypophosphorylation of Mdm2 in response to ionizing rays, and in consequence to p53 stabilization.
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Glycogen synthase kinase-3 also appears to inhibit p53 by enhancing its Mdm2-dependent degradation.
“Glycogen synthase kinase-3 (GSK3) also appears to inhibit p53 by enhancing its Mdm2-dependent degradation [68].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [68]
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Cites
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995) · Nature · doi:10.1038/378785a0 · Cited by 5,244 · see citing works
Live or let die: the cell's response to p53
Vousden, K. H., & Lü, X. (2002) · Nature reviews. Cancer · doi:10.1038/nrc864 · Cited by 3,177 · see citing works
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113 · see citing works
Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization
Diehl, J. A., Cheng, M., Roussel, M. F., & Sherr, C. J. (1998) · Genes & Development · doi:10.1101/gad.12.22.3499 · Cited by 2,130 · see citing works
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951 · see citing works
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,447 · see citing works
GSK3 takes centre stage more than 20 years after its discovery
FRAME, S., & COHEN, P. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3590001 · Cited by 1,433 · see citing works
Molecular cloning and expression of glycogen synthase kinase‐3/factor A.
Woodgett, J. R. (1990) · The EMBO Journal · doi:10.1002/j.1460-2075.1990.tb07419.x · Cited by 1,362 · see citing works
DNA Damage-Induced Activation of p53 by the Checkpoint Kinase Chk2
Hirao, A., Kong, Y., Matsuoka, S., Wakeham, A. C., Ruland, J., Yoshida, H., Liu, D., Elledge, S. J., & Mak, T. W. (2000) · Science · doi:10.1126/science.287.5459.1824 · Cited by 1,288 · see citing works
GSK3 takes centre stage more than 20 years after its discovery
Frame, S., & Cohen, P. (2001) · Biochemical Journal · doi:10.1042/bj3590001 · Cited by 997 · see citing works
Sutherland, C., Leighton, I. A., & Cohen, P. (1993) · Biochemical Journal · doi:10.1042/bj2960015 · Cited by 903 · see citing works
Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A
Fang, X., Yu, S. X., Lu, Y., Bast, R. C., Woodgett, J. R., & Mills, G. B. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.220413597 · Cited by 833 · see citing works
Chk2/hCds1 functions as a DNA damage checkpoint in G<sub>1</sub>by stabilizing p53
Chehab, N. H., Malikzay, A., Appel, M., & Halazonetis, T. D. (2000) · Genes & Development · doi:10.1101/gad.14.3.278 · Cited by 805 · see citing works
Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathwayPreprint
Amit, S., Hatzubai, A., Birman, Y., Andersen, J., Ben-Shushan, E., Mann, M., Ben‐Neriah, Y., & Alkalay, I. (2002) · Genes & Development · doi:10.1101/gad.230302 · Cited by 754 · see citing works
Pirh2, a p53-Induced Ubiquitin-Protein Ligase, Promotes p53 Degradation
Leng, R. P., Lin, Y., Ma, W., Wu, H., Lemmers, B., Chung, S., Parant, J. M., Lozano, G., Hakem, R., & Benchimol, S. (2003) · Cell · doi:10.1016/s0092-8674(03)00193-4 · Cited by 717 · see citing works
ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage
Maya, R., Balass, M., Kim, S.-T., Shkedy, D., Leal, J.-F. M., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., et al. (2001) · Genes & Development · doi:10.1101/gad.886901 · Cited by 716 · see citing works
The ubiquitin ligase COP1 is a critical negative regulator of p53
Dornan, D., Wertz, I. E., Shimizu, H., Arnott, D. P., Frantz, G. D., Dowd, P., Rourke, K. O., Koeppen, H., & Dixit, V. M. (2004) · Nature · doi:10.1038/nature02514 · Cited by 700 · see citing works
Mitogen inactivation of glycogen synthase kinase-3β in intact cells via serine 9 phosphorylation
Stambolic, V., & Woodgett, J. R. (1994) · Biochemical Journal · doi:10.1042/bj3030701 · Cited by 581 · see citing works
Alt, J. R., Cleveland, J. L., Hannink, M., & Diehl, J. A. (2000) · Genes & Development · doi:10.1101/gad.854900 · Cited by 535 · see citing works
Differential Regulation of Glycogen Synthase Kinase 3β by Insulin and Wnt Signaling
Ding, V. W., Chen, R., & McCormick, F. P. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005342200 · Cited by 428 · see citing works
Fiol, C. J., Mahrenholz, A. M., Wang, Y., Roeske, R. W., & Roach, P. J. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47901-x · Cited by 367 · see citing works
HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53
Linares, L. K., Hengstermann, A., Ciechanover, A., Müller, S., & Scheffner, M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2030930100 · Cited by 361 · see citing works
Esteller, M., & Herman, J. G. (2004) · Oncogene · doi:10.1038/sj.onc.1207316 · Cited by 326 · see citing works
Ubiquitination of p53 and p21 Is Differentially Affected by Ionizing and UV Radiation
Maki, C. G., & Howley, P. M. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.1.355 · Cited by 305 · see citing works
Judging a Protein by More Than Its Name: GSK-3
Woodgett, J. R. (2001) · Science s STKE · doi:10.1126/stke.2001.100.re12 · Cited by 279 · see citing works
Direct, activating interaction between glycogen synthase kinase-3β and p53 after DNA damage
Watcharasit, P., Bijur, G. N., Zmijewski, J. W., Song, L., Zmijewska, A. A., Chen, X., Johnson, G. V. W., & Jope, R. S. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.122062299 · Cited by 266 · see citing works
Glycogen Synthase Kinase-3β (GSK3β) Binds to and Promotes the Actions of p53
Watcharasit, P., Bijur, G. N., Song, L., Zhu, J., Chen, X., & Jope, R. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305870200 · Cited by 262 · see citing works
Qu, L.-K., Huang, S. H., Baltzis, D., Rivas-Estilla, A.-M., Pluquet, O., Hatzoglou, M., Koumenis, C., Taya, Y., Yoshimura, A., & Koromilas, A. E. (2004) · Genes & Development · doi:10.1101/gad.1165804 · Cited by 247 · see citing works
Sutherland, C. D., & Cohen, P. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)80112-6 · Cited by 238 · see citing works
Blattner, C., Sparks, A., & Lane, D. P. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.5.3704 · Cited by 213 · see citing works
Self-citationThe conserved PI3′K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila
Scanga, S. E., Ruel, L., Binari, R. C., Snow, B., Stambolic, V., Bouchard, D., Peters, M., Calvieri, B., Mak, T. W., Woodgett, J. R., et al. (2000) · Oncogene · doi:10.1038/sj.onc.1203739 · Cited by 195 · see citing works
Topors Functions as an E3 Ubiquitin Ligase with Specific E2 Enzymes and Ubiquitinates p53
Rajendra, R., Malegaonkar, D., Pungaliya, P., Marshall, H., Rasheed, Z. A., Brownell, J. E., Liu, L. F., Lutzker, S. G., Saleem, A., & Rubin, E. H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.c400300200 · Cited by 192 · see citing works
Multisite Phosphorylation and the Integration of Stress Signals at p53
Meek, D. W. (1998) · Cellular Signalling · doi:10.1016/s0898-6568(97)00119-8 · Cited by 185 · see citing works
Hypophosphorylation of Mdm2 Augments p53 Stability
Blattner, C., Hay, T., Meek, D. W., & Lane, D. P. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.17.6170-6182.2002 · Cited by 144 · see citing works
Self-citationTurenne, G. A., & Price, B. D. (2001) · BMC Cell Biology · doi:10.1186/1471-2121-2-12 · Cited by 138 · see citing works
[48] cDNA cloning and properties of glycogen synthase kinase-3
Robertwoodgett, J. (1991) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(91)00172-s · Cited by 132 · see citing works
Cocompartmentalization of p53 and Mdm2 Is a Major Determinant for Mdm2-Mediated Degradation of p53
Xirodimas, D. P., Stephen, C. W., & Lane, D. P. (2001) · Experimental Cell Research · doi:10.1006/excr.2001.5314 · Cited by 127 · see citing works
Yuan, H., Mao, J., Li, L., & Wu, D. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.43.30419 · Cited by 104 · see citing works
Involvement of the DNA Repair Protein hHR23 in p53 Degradation
Glockzin, S., Ogi, F.-X., Hengstermann, A., Scheffner, M., & Blattner, C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.8960-8969.2003 · Cited by 93 · see citing works
Self-citationApoptotic and Growth-Promoting Activity of E2F Modulated by MDM2
Loughran, Ö., & Thangue, N. B. L. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.6.2186-2197.2000 · Cited by 90 · see citing works
A post-ubiquitination role for MDM2 and hHR23A in the p53 degradation pathway
Brignone, C., Bradley, K., Kisselev, A. F., & Grossman, S. R. (2004) · Oncogene · doi:10.1038/sj.onc.1207540 · Cited by 73 · see citing works
Hay, T., & Meek, D. W. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01850-0 · Cited by 61 · see citing works
Winter, M., Milne, D., Dias, S., Kulikov, R., Knippschild, U., Blattner, C., & Meek, D. (2004) · Biochemistry · doi:10.1021/bi0489255 · Cited by 60 · see citing works
Blattner, C., Knebel, A., Radler‐Pohl, A., et al. (1994) · Environmental and Molecular Mutagenesis · doi:10.1002/em.2850240103 · Cited by 19 · see citing works
Self-citationAnalysis of Nuclear and Cytoplasmic Degradation of p53 in Cells after Stress
Joseph, T. W., & Moll, U. M. (2003) · Humana Press eBooks · doi:10.1385/1-59259-408-5:211 · Cited by 13 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [15]Glockzin, S., F. Ogi, A. Hengstermann, M. Scheffner, and C. Blattner. 2003. Stabilization of polyubiquitinated forms of p53 by the DNA repair protein hHR23. Mol. Cell. Biol. 23:8960-8969. [DOI] [PMC free article] [PubMed] [Google Scholar]
Cited by
Sorted by citations
The p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450 · see citing works
The role of ubiquitin modification in the regulation of p53
Hock, A. K., & Vousden, K. H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.05.022 · Cited by 168 · see citing works
Mdm2 facilitates the association of p53 with the proteasome
Kulikov, R., Letienne, J., Kaur, M., Grossman, S. R., Arts, J., & Blattner, C. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911716107 · Cited by 94 · see citing works
Self-citationGSK3 and p53 - is there a link in Alzheimer's disease?
Proctor, C. J., & Gray, D. A. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-7 · Cited by 80 · see citing works
Meek, D. W., & Hupp, T. R. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2009.10.005 · Cited by 76 · see citing works
The roles of MDM2 and MDMX phosphorylation in stress signaling to p53
Chen, J. (2012) · Genes & Cancer · doi:10.1177/1947601912454733 · Cited by 33 · see citing works
Muscle‐specific Perilipin2 down‐regulation affects lipid metabolism and induces myofiber hypertrophy
Conte, M., Armani, A., Conte, G., Serra, A., Franceschi, C., Mele, M., Sandri, M., & Salvioli, S. (2019) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12355 · Cited by 30 · see citing works
- Authors
- Kulikov, R., Boehme, K. A., & Blattner, C.
- Affiliations
- Karlsruhe Institute of Technology (DE)
- Corresponding author
- Blattner, Christine
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-08-01
- Volume
- 25
- Issue
- 16
- Pages
- 7170-7180
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1190268
- OpenAlex
- W2125553533
- Cited by
- 132
- References
- 46
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 4 · 2019: 1 · 2018: 11 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 11 · 2012: 11
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- glycogen synthase kinase-3, MDM2, p53, protein phosphorylation, p53 degradation, ionizing radiation, p21WAF-1, p53 stabilization, tumor suppressor regulation
- MeSH terms
- Alanine, Amino Acid Sequence, Animals, Cell Line, Electrophoresis, Polyacrylamide Gel, Gene Expression Regulation, Glutathione Transferase, Humans, Microscopy, Fluorescence, Molecular Sequence Data, Mutation, Nuclear Proteins, Peptides, Phosphorylation, Plasmids, Protein Binding, Proto-Oncogene Proteins, Radiation, Ionizing, RNA, Serine, Time Factors, Transfection, Blotting, Northern, Blotting, Western, Tumor Suppressor Protein p53, Protein Structure, Tertiary, Cell Cycle Proteins, COS Cells, Reverse Transcriptase Polymerase Chain Reaction, Ubiquitin, Glycogen Synthase Kinase 3, Cell Line, Tumor, Proteasome Endopeptidase Complex, Immunoprecipitation, Cyclin-Dependent Kinase Inhibitor p21, Mice, Proto-Oncogene Proteins c-mdm2
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