A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus
Open accessAbstract
The Mdm2 oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. To regulate p53, Mdm2 must gain nuclear entry, and the mechanism that induces this is now identified. Mitogen-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and its downstream target, the Akt/PKB serine-threonine kinase, results in phosphorylation of Mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of Mdm2 from the cytoplasm into the nucleus. Pharmacological blockade of PI3-kinase/Akt signaling or expression of dominant-negative PI3-kinase or Akt inhibits nuclear entry of Mdm2, increases cellular levels of p53, and augments p53 transcriptional activity. Expression of constitutively active Akt promotes nuclear entry of Mdm2, diminishes cellular levels of p53, and decreases p53 transcriptional activity. Mutation of the Akt phosphorylation sites in Mdm2 produces a mutant protein that is unable to enter the nucleus and increases p53 activity. The demonstration that PI3-kinase/Akt signaling affects Mdm2 localization provides insight into how this pathway, which is inappropriately activated in many malignancies, affects the function of p53.
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Akt phosphorylates Mdm2 on S166/S186 and allows Mdm2 to move from the cytoplasm to nuclear compartment.
“Akt has been shown to phosphorylate Mdm2 on S166/S186 and allow Mdm2 to move from the cytoplasm to nuclear compartment [74].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [74]
Akt also stimulates Mdm2 translocation to the nucleus, which can contribute to reduced p53-dependent transcription.
“Akt also stimulates Mdm2 translocation to the nucleus, which can contribute to reduced p53-dependent transcription [62,63].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [62]
Following growth factor stimulation, Akt phosphorylates Mdm2 at Ser166 and Ser186, which increases Mdm2 half-life and stimulates Mdm2-dependent p53 degradation.
“Following growth factor stimulation, Akt phosphorylates Mdm2 at Ser166 and Ser186 [62], which increases Mdm2 half-life and stimulates Mdm2-dependent p53 degradation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [62]
Phosphorylation of MDM2 at Ser166 and Ser186, and of MDMX at Ser367, leads to their stabilization and is associated with p53 inhibition.
“Phosphorylation of MDM2 at Ser166 and Ser186 (Ref. 32), and of MDMX at Ser367 (Ref. 33), leads to their stabilization, and is associated with p53 inhibition.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [32]
The authors failed to detect phosphorylation on Ser186.
“We failed to detect phosphorylation on Ser 186 , which was previously described by other groups (31,32).”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [31]
Mdm2 can be phosphorylated by PKB in vitro at Ser166 and Ser186, and this phosphorylation promotes nuclear entry of Mdm2.
“Indeed, it has been reported that Mdm2 could be phosphorylated by PKB in vitro at Ser 166 and Ser 186 , and this phosphorylation promotes the nuclear entry of Mdm2 (31,32).”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [31]
Both endogenous Mdm2 and transfected Mdm2 were exclusively located in the nucleus independent of phosphorylation status of Mdm2.
“both endogenous Mdm2 (Fig. 5A and Fig. 6, B and C) and transfected Mdm2 (31,51,60) were exclusively located in the nucleus independent of phosphorylation status of Mdm2.”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [31]
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Self-citation
- Authors
- Mayo, L. D., & Donner, D. B.
- Affiliations
- Indiana University School of Medicine (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-08-14
- Volume
- 98
- Issue
- 20
- Pages
- 11598-11603
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC58775
- OpenAlex
- W2068912983
- Cited by
- 1,230
- References
- 52
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 28 · 2023: 30 · 2022: 31 · 2021: 41 · 2020: 33 · 2019: 34 · 2018: 35 · 2017: 36 · 2016: 41 · 2015: 55 · 2014: 67 · 2013: 63 · 2012: 83
- FWCI
- 24.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca073023-05)
- National Cancer Institute (CA 67891, CA73023, R01CA067891)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Keywords
- MDM2, p53, phosphatidylinositol 3-kinase, Akt, PI3K/Akt signaling, nuclear translocation, serine phosphorylation, p53 transcriptional activity, tumor suppressor regulation, cell survival, cell cycle progression
- MeSH terms
- Amino Acid Sequence, Cell Line, Cell Nucleus, Cloning, Molecular, Cytoplasm, Humans, Infant, Newborn, Kidney, Molecular Sequence Data, Nuclear Proteins, Phosphorylation, Proto-Oncogene Proteins, Recombinant Proteins, Transfection, Translocation, Genetic, Tumor Cells, Cultured, Keratinocytes, Tumor Suppressor Protein p53, Mutagenesis, Site-Directed, Sequence Alignment, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Protein Transport, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-mdm2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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