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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Phosphorylation of AKT: a Mutational Analysis
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“Major targets of AKT include the TSC1-TSC2 (tuberous sclerosis) complex which mediates TORC1 (target of rapamycin complex 1) activation [6], the forkhead transcription factors FOXO1 (Forkhead box) and FOXO3a which regulate cell death, morphology and function as tumor suppressors [9-13], MDM2 (murine double minute) whi…”
Background
The central region of HDM2 provides a second binding site for p53
Yu, G. W., Rüdiger, S., Veprintsev, D. B., Freund, S. M. V., Fernández-Fernández, M. R., & Fersht, A. R. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510343103 · Cited by 139
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“In normal, p53 levels are low due to continuous MDM2-mediated ubiquitination and degradation.(42) Our results indicated that G-1 treatment significantly downregulated the mRNA of MDM2 and upregulated the mRNA and protein of p53 via a time-dependent manner.”
Background
RAS/RAF/MEK/ERK and PI3K/PTEN/AKT Signaling in Malignant Melanoma Progression and Therapy
Yajima, I., Kumasaka, M. Y., Thang, N. D., Goto, Y., Takeda, K., Yamanoshita, O., Iida, M., Ohgami, N., Tamura, H., Kawamoto, Y., et al. (2011) · Dermatology Research and Practice · doi:10.1155/2012/354191 · Cited by 141
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Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2
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“S166 and S186 are known to be phosphorylated by Akt, which activates the Mdm2-mediated degradation of p53 (22, 23).”
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New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response
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Induction of Akt Activity by Chemotherapy Confers Acquired Resistance
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“For example, Akt can phosphorylate Mdm2 to enhance its ubiquitin ligase activity and hence degradation of p53 [50].”
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miR-34a Repression in Proneural Malignant Gliomas Upregulates Expression of Its Target PDGFRA and Promotes Tumorigenesis
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“Indeed, earlier work has identified a potential conduit for such transcriptional regulation through p-AKT and p-MDM2 [15].”
BackgroundInfluential
Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency
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Akt Pathway Inhibitors
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Role of the Phosphatidylinositol-3-Kinase and Extracellular Regulated Kinase Pathways in the Induction of Hypoxia-Inducible Factor (HIF)-1 Activity and the HIF-1 Target Vascular Endothelial Growth Factor in Ovarian Granulosa Cells in Response to Follicle-Stimulating Hormone
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Preferential Inhibition of Akt and Killing of Akt-Dependent Cancer Cells by Rationally Designed Phosphatidylinositol Ether Lipid Analogues
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Targets Involved in the Anti-Cancer Activity of Quercetin in Breast, Colorectal and Liver Neoplasms
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p53 and the Carcinogenicity of Chronic InflammationPreprint
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“The inhibitory effect of PI3K/AKT-1 signaling on p53 activity can involve AKT-1mediated phosphorylation and inactivation of p53-regulated proapoptotic factors (Datta et al. 1997) as well as AKT-1-mediated phosphorylation of Mdm2 (Ogawara et al. 2002), which increases p53 degradation.”
BackgroundInfluential
Signaling, metabolism, and cancer: An important relationship for therapeutic intervention
Vaghari‐Tabari, M., Ferns, G. A., Qujeq, D., Andevari, A. N., Sabahi, Z., & Moein, S. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30276 · Cited by 126
“on some proapoptotic proteins such as Bad and the well‐known tumor suppressor p53 causes resistance to apoptosis (Datta et al., 1997; Gottlieb et al., 2002; Ogawara et al., 2002).”
Background
A cell penetrating peptide derived from azurin inhibits angiogenesis and tumor growth by inhibiting phosphorylation of VEGFR-2, FAK and Akt
Mehta, R. R., Yamada, T., Taylor, B. N., Christov, K. T., King, M. L., Majumdar, D., Lekmine, F., Tiruppathì, C., Shilkaitis, A. L., Bratescu, L., et al. (2011) · Angiogenesis · doi:10.1007/s10456-011-9220-6 · Cited by 115
“Akt-mediated phosphorylation of MDM2 decreases its association with p53, reducing the rate of its degradation [50, 55].”
BackgroundInfluential
Tumor Suppressor p53 Alters Host Cell Metabolism to Limit Chlamydia trachomatis Infection
Siegl, C., Prusty, B. K., Rajeeve, K., Wischhusen, J., & Rudel, T. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.004 · Cited by 116
“Akt directly activates HDM2 by phosphorylation of Ser166 and Ser186 (Ogawara et al., 2002), and in agreement with this, we found increased phosphorylated HDM2 in infected cells (Figures 3A and 3B).”
Background
Autophagy is upregulated in ovarian endometriosis: a possible interplay with p53 and heme oxygenase-1
Allavena, G., Carrarelli, P., Bello, B. D., Luisi, S. V., Petraglia, F., & Maellaro, E. (2015) · Fertility and Sterility · doi:10.1016/j.fertnstert.2015.02.007 · Cited by 110
“To explain the p53 down-regulation, two major autophagy-independent mechanisms can be evoked, both related to Akt pathway, the latter proved to be overactivated in endometriotic tissues and cells from ovarian endometriomas (25, 26): the first mechanism is the transcriptional down-regulation of p53, through Akt-mediate…”
Background
Plumbagin inhibits tumorigenesis and angiogenesis of ovarian cancer cells in vivo
Sinha, S., Pal, K., Elkhanany, A. M., Dutta, S. K., Cao, Y., Mondal, G., Iyer, S. R., Somasundaram, V., Couch, F. J., Shridhar, V., et al. (2012) · International Journal of Cancer · doi:10.1002/ijc.27724 · Cited by 109
Myocardial Aging and Senescence: Where Have the Stem Cells Gone?
Sussman, M. A., & Anversa, P. (2004) · Annual Review of Physiology · doi:10.1146/annurev.physiol.66.032102.140723 · Cited by 105
Regulation of the p53-MDM2 pathway by 14-3-3 σ and other proteins
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The eIF2α Kinases PERK and PKR Activate Glycogen Synthase Kinase 3 to Promote the Proteasomal Degradation of p53
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Regulation of p53 - insights into a complex process
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“Due to the increase in Mdm2 abundance, p53 degradation is enhanced upon Akt/PKB activation (Mayo and Donner, 2001; Zhou et al., 2001; Ashcroft et al., 2002; Ogawara et al., 2002; Feng et al., 2004; Danes et al., 2008).”
Background
Targeting prostate cancer based on signal transduction and cell cycle pathways
Lee, J. T., Lehmann, B. D., Terrian, D. M., Chappell, W. H., Stivala, F., Libra, M., Martelli, A. M., Steelman, L. S., & McCubrey, J. A. (2008) · Cell Cycle · doi:10.4161/cc.7.12.6166 · Cited by 104
The Trk A, B, C's of Neurotrophins in the Cochlea
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“For example, Akt phosphorylates and inactivates proapoptotic transcription factors of the Forkhead/FoxO family (Brunet et al., 1999) and p53 (Ogawara et al., 2002) and Akt phosphorylates and inactivates the proapoptotic Bcl-2 family protein Bad (Downward, 1999).”
Background
Sumoylation of Mdm2 by Protein Inhibitor of Activated STAT (PIAS) and RanBP2 Enzymes
Miyauchi, Y., Yogosawa, S., Honda, R., Nishida, T., & Yasuda, H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208319200 · Cited by 102
Molecular determinants of Akt-induced keratinocyte transformation
Segrelles, C., Moral, M., Lara, M. F., Ruiz, S., Santos, M., Leis, H., García‐Escudero, R., Martínez‐Cruz, A. B., Martínez‐Palacio, J., Hernández, P., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1209155 · Cited by 101
“In addition, Akt can also phosphorylate mdm2, favoring mdm2–p53 association and leading to subsequent p53 degradation (Mayo and Donner, 2001; Ogawara et al., 2002; Zhou and Hung, 2002).”
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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