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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The p53-Mdm2 Loop: A Critical Juncture of Stress Response
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Background
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“This is correlated with an increase of phospho-pan-Akt (pAkt), and the increased levels of phospho-GSK3β (pGSK3β) and phospho-Mdm2 (pMdm2), a direct indication of increased Akt kinase activity (Alarcon-Vargas and Ronai, 2002; Cross et al., 1995; Ogawara et al., 2002) (Fig.”
Background
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“Only if activated, Akt mediates phosphorylation of the p53 primary inhibitor, Mdm2, allowing it to localize to the nucleus and prime p53 for degradation [74,75].”
Background
Gene expression profiling reveals the role of RIG1 like receptor signaling in p53 dependent apoptosis induced by PUVA in keratinocytes
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Tian, X., Liu, F., Zhang, X. P., Li, J., & Wang, W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038164 · Cited by 32
“Both Mdm2c and Mdm2Pc induce the ubiquitination of p53 with the same efficiency [31].”
Background
Loss of cell adhesion molecule L1 like promotes tumor growth and metastasis in esophageal squamous cell carcinoma
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“In addition, Akt inhibits p53 nuclear accumulation and activity by inhibiting the p53 content and activity (phosphorylation), disturbing its subcellular localization, and promoting its ubiquitindependent proteolysis (Gottlieb et al., 2002; Ogawara et al., 2002) In this study, both DPP and kaempferol, administered indi…”
Background
From Melanoma Development to RNA-Modified Dendritic Cell Vaccines: Highlighting the Lessons From the Past
Shadbad, M. A., Hajiasgharzadeh, K., Derakhshani, A., Silvestris, N., Baghbanzadeh, A., Racanelli, V., & Baradaran, B. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.623639 · Cited by 33
“The P-16, via repression of cyclindependent kinases/cyclin D complexes, mediates the cross-talk between the P53 and Rb (28).”
BackgroundInfluential
Long isoform of ErbB3 binding protein, p48, mediates protein kinase B/Akt-dependent HDM2 stabilization and nuclear localization
Kim, C. K., Lee, S. B., Nguyen, T. L. X., Lee, K.-H., Um, S. H., Kim, J., & Ahn, J. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.08.013 · Cited by 32
“Phosphorylation of HDM2 by Akt leads to inhibition of HDM2 self-ubiquitination, stabilizing HDM2 and enhancing HDM2dependent p53 degradation [23–25].”
Background
The Clustered, Regularly Interspaced, Short Palindromic Repeats-associated Endonuclease 9 (CRISPR/Cas9)-created MDM2 T309G Mutation Enhances Vitreous-induced Expression of MDM2 and Proliferation and Survival of Cells
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“For example, Akt, a protein kinase, enhances MDM2-mediated ubiquitination and degradation of p53 by promoting MDM2 phosphorylation at serine 186 (27).”
Background
The Oncoprotein SS18-SSX1 Promotes p53 Ubiquitination and Degradation by Enhancing HDM2 Stability
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“Phosphorylation of HDM2 by Akt promotes its nuclear localization, resulting in enhanced stability and increased p53 ubiquitination and degradation (46, 47).”
Background
Asrij/OCIAD1 suppresses CSN5-mediated p53 degradation and maintains mouse hematopoietic stem cell quiescence
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(3-Chloroacetyl)-indole, a Novel Allosteric AKT Inhibitor, Suppresses Colon Cancer Growth In Vitro and In Vivo
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HIV-1 Nef promotes ubiquitination and proteasomal degradation of p53 tumor suppressor protein by using E6AP
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“the PI3K/Akt survival pathway has been reported to prevent p53 activation and p53-dependent apoptosis, [17,18] loss of GPR87 may trigger a decrease of Akt expression, which stabilizes the E3 ubiquitin ligase Mdm2, thereby inducing an increase in the level of p53 via the PI3K/Akt survival pathway.”
Background
The Diarylheptanoid Hirsutenone Sensitizes Chemoresistant Ovarian Cancer Cells to Cisplatin via Modulation of Apoptosis-inducing Factor and X-linked Inhibitor of Apoptosis
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“A, Akt appears to inhibit apoptosis by stabilizing both XIAP and MDM2 at the protein level via direct phosphorylation of these proteins (12, 30).”
Background
Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming
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“(2) Akt has been shown to activate Mdm2 (35) and facilitate Mdm2-mediated ubiquitination and degradation of p53 (29).”
Background
Recent Progress in Mouse Models for Tumor Suppressor Genes and its Implications in Human Cancer
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“Accordingly, the expression levels of MDM2, an E3 ubiquitin ligase of TP53, and its upstream regulators, AKT and pAKT1(S473) (26), were next examined.”
Background
DNA damage and apoptosis induced by a potent orally podophyllotoxin derivative in breast cancer
Wang, Y., Sun, H., Xiao, Z., Zhang, G., Zhang, D., Bao, X., Li, F., Wu, S., Gao, Y., & Wei, N. (2018) · Cell Communication and Signaling · doi:10.1186/s12964-018-0263-9 · Cited by 30
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“Also, the PI3K/AKT signaling pathway inhibits P53-mediated apoptosis in different types of cancer, through its effect on P53 ubiquitination by murine double minute 2 (MDM2) (Abraham & O'Neill, 2014; Ogawara et al., 2002; Qiu et al., 2010).”
Background
G Protein-Coupled Receptor 87: a Promising Opportunity for Cancer Drug Discovery.
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Selenocysteine derivative overcomes TRAIL resistance in melanoma cells: evidence for ROS-dependent synergism and signaling crosstalk
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“The activated Akt mediates cell growth via the phosphorylation of many substrates including Bax [46], Bad [47], MDM2 [48] and FOXO transcription factors, which can regulate the expression of Bim [49].”
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“To test the role of PI3-kinase in BEL-induced Akt phos- 64 Sun et al. phorylation, we pretreated cells with LY294002, a PI3-kinase inhibitor demonstrated to decrease Akt phosphorylation in response to numerous stimuli (Ogawara et al., 2002; Pommery and Henichart, 2005; Liu et al., 2006).”
BackgroundMethod
Positive Effects of PI3K/Akt Signaling Inhibition on PTEN and P53 in Prevention of Acute Lymphoblastic Leukemia Tumor Cells
Naderali, E., Valipour, B., Khaki, A. A., Rad, J. S., Alihemmati, A., Rahmati, M., & Charoudeh, H. N. (2019) · Advanced Pharmaceutical Bulletin · doi:10.15171/apb.2019.056 · Cited by 29
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“4E).(38,136) Thus, PTEN is involved in the stabilization and transcriptional activity of p53, which has an important function in tumorigenesis.”
Exposure to High-Dose Diesel Exhaust Particles Induces Intracellular Oxidative Stress and Causes Endothelial Apoptosis in Cultured In Vitro Capillary Tube Cells
Tseng, C., Wang, J.-S., Chang, Y., Chang, J.-F., & Chao, M. (2014) · Cardiovascular Toxicology · doi:10.1007/s12012-014-9302-y · Cited by 29
“tosis [47, 48].”
High temperature suppressed SSC self-renewal through S phase cell cycle arrest but not apoptosis
Wang, J., Gao, W.-J., Deng, S., Liu, X., Jia, H., & Ma, W. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1335-5 · Cited by 28
“In the PI3K/AKt signalling pathway, Akt can bind to MDM2 to phosphorylate its Ser166 and Ser186 sites and induce nuclear import or upregulate ubiquitin ligase activity, thereby promoting P53 inactivation or degradation and blocking P53-mediated transcription reaction [45, 46].”
Background
MDM2 phosphorylation mediates H2O2-induced lens epithelial cells apoptosis and age-related cataract
Wang, Z., Su, D., Sun, Z., Liu, S., Sun, L., Li, Q., Guan, L., Liu, Y. U., Ma, X., & Hu, S. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.05.060 · Cited by 28
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“A similar transition mode has been reported previously (21, 36).”
Method
MDM2 regulates a novel form of incomplete neoplastic transformation of Theileria parva infected lymphocytes
Hayashida, K., Kajino, K., Hattori, M., Wallace, M., Morrison, I. W., Greene, M. I., & Sugimoto, C. (2012) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2012.08.008 · Cited by 28
“Phosphorylation of MDM2 by Akt/PKB has been reported to result in nuclear translocation of MDM2 (Mayo and Donner, 2001), enhancement of MDM2-mediated ubiquitination of p53 (Ogawara et al., 2002), and stabilization of MDM2 by preventing self-ubiquitination (Feng et al., 2004).”
Epstein-Barr virus Latent Membrane Protein LMP1 reduces p53 protein levels independent of the PI3K-Akt pathway
Husaini, R., Ahmad, M., & Khoo, A. S. B. (2011) · BMC Research Notes · doi:10.1186/1756-0500-4-551 · Cited by 27
“Akt activation has been shown to phosphorylate MDM2 and induces its migration into the nucleus where it binds, ubiquitinates and degrades p53 protein resulting in a lower level of p53 protein [30].”
Background
Alterations of ubiquitin related proteins in the pathology and development of schizophrenia: Evidence from human and animal studies
Andrews, J. L., Goodfellow, F. J., Matosin, N., Snelling, M., Newell, K. A., Huang, X., & Fernandez, F. (2017) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2017.01.009 · Cited by 28

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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