Cited by 132Cancer-related Molecular PathwaysPI3K/AKT/mTOR signaling in cancerUbiquitin and proteasome pathways

Glycogen synthase kinase 3-dependent phosphorylation of Mdm2 regulates p53 abundance

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Kulikov, Roman, Boehme, Karen A., Blattner, Christine·2005·Molecular and Cellular Biology

Abstract

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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Crossref · 10.1128/mcb.25.16.7170-7180.2005

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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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  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]

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Authors
Kulikov, R., Boehme, K. A., & Blattner, C.
Affiliations
Karlsruhe Institute of Technology (DE)
Corresponding author
Blattner, Christine
Venue
Molecular and Cellular Biology
Published
2005-08-01
Volume
25
Issue
16
Pages
7170-7180
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
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
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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