Cited by 617Cancer-related Molecular PathwaysUbiquitin and proteasome pathwaysPI3K/AKT/mTOR signaling in cancer

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Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53

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Ogawara, Yoko, Kishishita, Shohei, Obata, Toshiyuki, Isazawa, Yuko, Suzuki, Toshiaki, Tanaka, Keiji, Masuyama, Norihisa, Gotoh, Yukiko·2002·Journal of Biological Chemistry

DOI 10.1074/jbc.m109745200

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Abstract

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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Additional file 5 of Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo
Huang, H., Park, S., Zhang, H., Park, S., Kwon, W., Kim, E., Zhang, X., Jang, S., Yoon, D. H., Choi, S.-K., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14344420
Additional file 1 of Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo
Huang, H., Park, S., Zhang, H., Park, S., Kwon, W., Kim, E., Zhang, X., Jang, S., Yoon, D. H., Choi, S.-K., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14344408
Additional file 1 of Integrated high-throughput small RNA and transcriptome sequencing unveil the shape-dependent toxicity of nano-alumina in rat astrocytes
Chen, Y., Dong, L., Deng, F., Cao, Y., Fu, Y., Zhu, M., Qin, G., Schultz, D. R., Shekh, K., & Tang, S. (2021) · Figshare · doi:10.6084/m9.figshare.15179362
Additional file 2 of Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo
Huang, H., Park, S., Zhang, H., Park, S., Kwon, W., Kim, E., Zhang, X., Jang, S., Yoon, D. H., Choi, S.-K., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14344411
Additional file 4 of Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo
Huang, H., Park, S., Zhang, H., Park, S., Kwon, W., Kim, E., Zhang, X., Jang, S., Yoon, D. H., Choi, S.-K., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14344417
Additional file 6 of Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo
Huang, H., Park, S., Zhang, H., Park, S., Kwon, W., Kim, E., Zhang, X., Jang, S., Yoon, D. H., Choi, S.-K., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14344423
Effect of Quizartinib on the Resistance of Acute Myeloid Leukemia Cells with FLT3-ITD-Positive and FLT3-ITD-Negative Phenotypes to the TRAIL-Induced Apoptosis
Kobyakova, M. I., Lomovskaya, Y. V., Krasnov, K. S., Odinokova, I. V., Мещерякова, Е. Ю., Ermakov, A. M., Didenko, A. S., Сенотов, А. С., Fadeeva, I. S., & Фадеев, Р. С. (2026) · Biochemistry (Moscow) · doi:10.1134/s000629792560276x
“Alternative activation of the Akt signaling pathway upon FLT3 inhibition could suppress the p38-MAPK pathway [84, 85] and the p53-dependent cascade through phosphorylation of MDM2 [86], as well as contribute to activation of the ErbB signaling pathway [87, 88].”
Rôle pro-tumorigénique de HACE1 dans le mélanome
Hachem, N. E. (2017) · theses.fr (ABES) · doi:10.70675/c29467dezf843z4a4cz91a8z8b39a51c97c6
Identification des mécanismes moléculaires et cellulaires sous jacents à la perte de Pten dans l’épithélium prostatique murin et étude du rôle de la Vitamine D dans la carcinogenèse prostatique
Grelet, É. (2018) · theses.fr (ABES) · doi:10.70675/acc680a1zecfdz4c85z8f27z1fd05d90a500
CLEC12B un gène de la famille des lectines impliqué dans le processus de melanomagénèse en agissant comme un gène suppresseur de tumeurs : CLEC12B un gène suppresseur de tumeurs impliqué dans le mélanome
Montaudié, H. (2019) · theses.fr (ABES) · doi:10.70675/f1484b7fz6f0bz40c7z928bz7df41933fe39

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
ORCID: Suzuki, Toshiaki
Tanaka, Keiji
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)
DOI: 10.1074/jbc.m109745200
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6719 d)
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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Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53

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