The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53
Open accessAbstract
p53 plays a key role in DNA damage-induced apoptosis. Recent studies have reported that the phosphatidylinositol 3-OH-kinase-Akt pathway inhibits p53-mediated transcription and apoptosis, although the underlying mechanisms have yet to be determined. Mdm2, a ubiquitin ligase for p53, plays a central role in regulation of the stability of p53 and serves as a good substrate for Akt. In this study, we find that expression of Akt reduces the protein levels of p53, at least in part by enhancing the degradation of p53. Both Akt expression and serum treatment induced phosphorylation of Mdm2 at Ser186. Akt-mediated phosphorylation of Mdm2 at Ser186 had little effect on the subcellular localization of Mdm2. However, both Akt expression and serum treatment increased Mdm2 ubiquitination of p53. The serum-induced increase in p53 ubiquitination was blocked by LY294002, a phosphatidylinositol 3-OH-kinase inhibitor. Moreover, when Ser186 was replaced by Ala, Mdm2 became resistant to Akt enhancement of p53 ubiquitination and degradation. Collectively, these results suggest that Akt enhances the ubiquitination-promoting function of Mdm2 by phosphorylation of Ser186, which results in reduction of p53 protein. This study may shed light on the mechanisms by which Akt promotes survival, proliferation, and tumorigenesis.
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“We and other groups (58) did not observe significant changes in the subcellular localization of Mdm2 when PKB was activated by a variety of stimuli (data not shown).”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [58]
Citations
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Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways
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PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside
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Metadata
- Authors
- Ogawara, Y., Kishishita, S., Obata, T., Isazawa, Y., Suzuki, T., Tanaka, K., Masuyama, N., & Gotoh, Y.
- Affiliations
- Institute for Quantitative Biosciences, The University of Tokyo (JP)
- Tokushima University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Gotoh, Yukiko
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 277
- Issue
- 24
- Pages
- 21843-21850
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2027217537
- Semantic Scholar
- bca1d1791eb8e2056d050c2ab2b91129d0d06de7
- Cited by
- 617
- References
- 60
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 11 · 2023: 19 · 2022: 19 · 2021: 34 · 2020: 29 · 2019: 28 · 2018: 33 · 2017: 31 · 2016: 36 · 2015: 28 · 2014: 35 · 2013: 43 · 2012: 29
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- Akt, MDM2, p53, ubiquitination, protein degradation, PI3K/Akt signaling, p53 stabilization, LY294002, carcinogenesis, apoptosis
- MeSH terms
- Cell Survival, Chromones, Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Microscopy, Fluorescence, Morpholines, Nuclear Proteins, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Proto-Oncogene Proteins, Recombinant Proteins, RNA, Messenger, Serine, Subcellular Fractions, Time Factors, Tumor Cells, Cultured, Blotting, Western, Retroviridae Proteins, Oncogenic, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, Ubiquitin, Proto-Oncogene Proteins c-akt, Oncogene Protein v-akt, Proto-Oncogene Proteins c-mdm2
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