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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Background
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Background
Isotretinoin treatment upregulates the expression of p53 in the skin and sebaceous glands of patients with acne vulgarisPreprint
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“A recent study revealed that FGF21 maintained normal spontaneous germ-cell apoptosis by activating AKT1, which further phosphorylated murine double minute 2 (MDM2) at Ser166 and Ser186, thus increasing p53 ubiquitination and degradation [90,94] ( Fig.”
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CD 133 and CD 133‐regulated nucleophosmin linked to 5‐fluorouracil susceptibility in human colon cancer cell line SW 620
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MAP kinase protects G protein-coupled receptor kinase 2 from proteasomal degradation
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The human adenovirus PI3K-Akt activator E4orf1 is targeted by the tumor suppressor p53
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“Equally, Mdm2, which increases p53 degradation upon Akt activation (124, 125), was cleaved similarly during HAdV-C5 WT and ∆E4orf1 infections.”
Method
In vitro anticancer study of novel curcumin derivatives via targeting PI3K/Akt/p53 signaling pathway
Zhou, H., Wu, Z., Zhang, Y., Yu, Z., Nie, Z., Fan, J., Zhu, Z., Chen, F., & Wang, T. (2024) · Molecular Diversity · doi:10.1007/s11030-024-10833-9 · Cited by 6
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Midori‐ishi Cyan/monomeric Kusabira‐Orange‐based fluorescence resonance energy transfer assay for characterization of various E3 ligases
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“…(Kim et al. 2004). pGEX-6P-1-TRAF6 RZ1-3 was used as described (Yin et al. 2009). pGEX-6P-1-MDM2 was Genes to Cells (2016) 21, 608–623 © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd kindly provided by Dr. Y. Goto (University of Tokyo) (Ogawara et al. 2002).”
MethodInfluential
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“In the following sections, we first detail how we built an underlying gene regulatory network of mammalian cellular aging based on the existing experimental literature (Haruta et al., 2000; Stambolic et al., 2001; Inoki et al., 2002, 2003; Ogawara et al., 2002; Kong, 2004; Lahav et al., 2004; Nemoto, 2004; You et al.,…”
Method
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Overexpression of LINC00673 Promotes the Proliferation of Cervical Cancer Cells
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“When activated by AKT phosphorylation, MDM2 translocates to the nucleus and binds to the p53 tumor suppressor, promoting p53 degradation and thus promoting cell survival (24, 25).”
Background
Celecoxib Treatment Alters p53 and MDM2 Expression via COX-2 Crosstalk in A549 Cells.
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An Overview of the Oncogenic Signaling Pathways in Different Types of CancersPreprint
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“Moreover, AKT inhibits the forkhead box (FoxO) reliant transcription of cell cycle inhibitors, including RBL2 (retinoblastoma-like protein 2) and p27 [52], thereby stimulating phosphorylation mouse double minute 2 homolog (MDM2) [53], the ubiquitin ligase, prompts p53 Preprints (www.”
Background
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Higher expression of human telomerase reverse transcriptase in productively‐infected CD4 cells possibly indicates a mechanism for persistence of the virus in HIV infection
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“Researchers have shown that AKT enhances P53 degradation (37) and that a P53-dependent pathway affects hTERT expression (38) suggesting interlinking of these mechanisms.”
Background
Molecular and cellular evidence for hsa‐miR‐1254 suppressor effect against HER2 signaling in breast cancer
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“P53 is inhibited by AKT via MDM2 [18].”
Influential
Low daunomycin concentrations protect colorectal cancer cells from hypoxia-induced apoptosis
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“Activated phospho-Akt (P-Akt) has been shown to protect normal and tumoral cells against hypoxia and p53-induced apoptosis (Ogawara et al., 2002).”
Background
Oncogenic Signaling Pathways in Cancer: An OverviewPreprint
Derakhshani, A., Rostami, Z., Taefehshokr, S., Safarpour, H., Astamal, R. V., Taefehshokr, N., Alizadeh, N., Argentiero, A., Silvestris, N., & Baradaran, B. (2020) · Preprints.org · doi:10.20944/preprints202003.0201.v1 · Cited by 4
“Furthermore, the ubiquitylation and degradation of p53 initiated by AKT repress apoptosis induced by p53 [53].”
Background
The FBP1‐TP53‐NRF2 metabolic switch in metabolic dysfunction‐associated steatohepatitis‐hepatocellular carcinoma progression and senescence reversal
Zhu, Y., Wei, D., Karin, M., & Gu, L. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70293 · Cited by 4
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Ortega‐Camarillo, C., Flores-López, L. A., & Ávalos‐Rodríguez, A. (2015) · Immunoendocrinology · doi:10.14800/ie.1075 · Cited by 4
Akt Phosphorylation Orchestrates T11TS Mediated Cell Cycle Arrest in Glioma Cells
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“Increasing the ubiquitin ligase activity of Mdm2 Akt results in the degradation of p53 and reduces the p53-mediated pro-apoptotic transcriptional response (30).”
Background
Bone marrow overexpression of SNAI1 is an early indicator of intrinsic drug resistance in patients with de novo acute myeloid leukemia
Gouda, M. B. Y., Hassan, N. M., & Kandil, E. (2022) · The Journal of Gene Medicine · doi:10.1002/jgm.3443 · Cited by 4
Unveiling the role of circRBBP7 in myoblast proliferation and differentiation: A novel regulator of muscle development
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“44 MDM2 constantly monoubiq-uitinates p53 and thus is the critical step in mediating its degradation by nuclear and cytoplasmic proteasomes.”
Integrated high-throughput small RNA and transcriptome sequencing unveil the shape-dependent toxicity of nano-alumina in rat astrocytes
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Serdemetan promotes bone regeneration via coordinated regulation of osteoblast and osteoclast activity
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Guven‐Maiorov, E., Sakakibara, N., Ponnamperuma, R. M., Dong, K., Matar, H., King, K. E., & Weinberg, W. C. (2022) · Molecular Carcinogenesis · doi:10.1002/mc.23405 · Cited by 3
“47,48 52 The interaction of MDM2 with the TAD of p73 and p53 has been well documented and supported experimentally.”
Background
Inorganic arsenic induces MDM2, p53, and their phosphorylation and affects the MDM2/p53 complex in vitro
Yin, J., Zhou, Q., Tan, J., Che, W., & He, Y. (2022) · Environmental Science and Pollution Research · doi:10.1007/s11356-022-21986-1 · Cited by 3
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The Competition of Yin and Yang: Exploring the Role of Wild-Type and Mutant p53 in Tumor Progression
Cai, B., Sung, Y.-T., Chen, C., Shaw, J., & Hsin, I. (2023) · Biomedicines · doi:10.3390/biomedicines11041192 · Cited by 3
“Additionally, AKT can phosphorylate MDM2, leading to the degradation of wild type p53 [22].”
Background
Correlation Between Akt and p53 Protein Expression and Chemoradiotherapy Response in Cervical Cancer Patients
Kurnia, I., Siregar, B., Soetopo, S., Ramli, I., Kurjana, T., Andriono, Tobing, M. D. L., Suryawathi, B., Kisnanto, T., & Tetriana, D. (2014) · HAYATI Journal of Biosciences · doi:10.4308/hjb.21.4.173 · Cited by 3
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Background
Integrative machine learning approach for identification of new molecular scaffold and prediction of inhibition responses in cancer cells using multi-omics data
Kaushik, A. C., Talware, S. K., & Siddiqi, M. I. (2025) · Briefings in Functional Genomics · doi:10.1093/bfgp/elaf006 · Cited by 3
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“In the body, apoptosis due to aging or other factors is closely associated with muscle or hearing loss [26, 27]. p53 is a key regulator of mitochondria-dependent apoptosis and the transcriptional activity of p53 is inhibited by the PI3K/AKT pathway [28, 29].”
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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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