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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“According to some studies, Akt phosphorylates (and hence activates) Mdm2 at the serine residues 166 and 186 [125–127], however, phosphorylation of the latter site was not observed in [128,129].”
BackgroundResult
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Background
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Background
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Background
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Background
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“It is reasonable since Akt enhances MDM2 mediated proteasome degradation always fails for mutant p53 [39].”
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Background
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“On the other hand, p53 degradation is mainly facilitated through mdm2, the major p53 ubiquitin ligase, leading to ubiquitin-dependent proteasomal degradation of p53 (Lakin and Jackson, 1999; Ogawara et al., 2002).”
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Phosphorylation by COP9 Signalosome‐Associated CK2 Promotes Degradation of p27 during the G1 Cell Cycle Phase
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“35 AKT is also known to provide progrowth and survival signals through several pathways, including DNA damage repair, 36 cell cycling, 37 degradation of p53, 38 and receptor tyrosine kinase signal modulation.”
Background
Advancements in dual-target inhibitors of PI3K for tumor therapy: Clinical progress, development strategies, prospects
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“Downmodulation of p53 expression levels may be, in part, contributed to by Akt as Akt enhances Mdm2-mediated ubiquitination and degradation of p53 (Ogawara et al., 2002).”
Background
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“Existing evidence suggests that Akt activation induces negative control of p53 levels through enhancing MDM2 (22).”
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“It is well established that Akt phosphorylates the E3 ubiquitin ligase MDM2 proto-oncogene, enhancing MDM2-mediated degradation of p53 by ubiquitination (19).”
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“Mouse double minute 2 homolog (MDM2), encoded by the MDM2 gene, is a ubiquitin ligase that functions as an important negative regulator of p53 [2].”
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“According to findings, in glioblastoma, phosphorylated AKT can enhance the expression of MDM2; a pro-oncogene downstream of AKT pathway (99).”
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Palmitic Acid Methyl Ester Induces G2/M Arrest in Human Bone Marrow-Derived Mesenchymal Stem Cells via the p53/p21 Pathway
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“It has been shown that Akt, a protein serine/threonine kinase involved in regulating cell growth, proliferation, and apoptosis processes, can enhance the Mdm2-mediated ubiquitination and degradation of p53 [59].”
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ADNP Upregulation Promotes Bladder Cancer Cell Proliferation via the AKT Pathway
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“The p53 pathway is a second major pathway involved in cancer, and MDM2 is a direct regulator of p53 (Ogawara et al. 2002).”
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Cell Death and Cochlear Protection
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LETM1 Promotes Gastric Cancer Cell Proliferation, Migration, and Invasion via the PI3K/Akt Signaling Pathway
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CoCl2 induces PC12 cells apoptosis through p53 stability and regulating UNC5B
Lee, M., Kang, H., & Jang, S. (2013) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2013.04.007 · Cited by 16
Expression of Akt and Mdm2 in human esophageal squamous cell carcinoma
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Zinc Trisulphonated Phthalocyanine Used in Photodynamic Therapy of Dysplastic Oral Keratinocytes
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Down-regulation of hTERT and Cyclin D1 transcription via PI3K/Akt and TGF-β pathways in MCF-7 Cancer cells with PX-866 and Raloxifene
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“Activated Akt activates the cell cycle by blocking, through phosphorylation, the interaction between MDM2 and p14 (p19) that would prevent ubiquitin-mediated proteolysis of p53 [16-17] and by the mTOR-mediated degradation of cMYC competitor MAD1 [18-19].”
Background
MDM2 and PSMA Play Inhibitory Roles in Metastatic Breast Cancer Cells Through Regulation of Matrix Metalloproteinases.
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Cyclo‐glycylproline attenuates hydrogen peroxide‐induced cellular damage mediated by the MDM2‐p53 pathway in human neural stem cells
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Background
Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5F cells
Barzalobre-Geronimo, R., Flores-López, L. A., Baiza-Gutman, L. A., Cruz, M., García-Macedo, R., Ávalos‐Rodríguez, A., Contreras‐Ramos, A., Díaz-Flores, M., & Ortega‐Camarillo, C. (2015) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-015-2416-0 · Cited by 14
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“In addition, MDM2-mediated p53 ubiquitination and degradation can be modulated by the PI3K/AKT signaling pathway [28].”
Background
Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species
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“On the other hand, AKT promotes cell survival by activating the stress protein kinase pathways (SAPK), MAPK kinase pathway and JNK pathway [43], enhancing the Mdm2mediated ubiquitination and degradation of p53 [44], or by phosphorylating transcriptional factors such as FoxOs or NF-κβ [45] that regulate the expression…”
Background

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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