PTEN Protects p53 from Mdm2 and Sensitizes Cancer Cells to Chemotherapy
Open accessAbstract
The PTEN tumor suppressor protein inhibits phosphatidylinositol 3-kinase (PI3K)/Akt signaling that promotes translocation of Mdm2 into the nucleus. When restricted to the cytoplasm, Mdm2 is degraded. The ability of PTEN to inhibit the nuclear entry of Mdm2 increases the cellular content and transactivation of the p53 tumor suppressor protein. Retroviral transduction of PTEN into U87MG (PTEN null) glioblastoma cells increases p53 activity and expression of p53 target genes and induces cell cycle arrest. U87MG/PTEN glioblastoma cells are more sensitive than U87MG/PTEN null cells to death induced by etoposide, a chemotherapeutic agent that induces DNA damage. Previously, tumor suppressor proteins have been supposed to act individually to suppress cancers. Our results establish a direct connection between the activities of two major tumor suppressors and show that they act together to respond to stresses and malignancies. PTEN protects p53 from survival signals, permitting p53 to function as a guardian of the genome. By virtue of its capacity to protect p53, PTEN can sensitize tumor cells to chemotherapy that relies on p53 activity. p53 induces PTEN gene expression, and here it is shown that PTEN protects p53, indicating that a positive feedback loop may amplify the cellular response to stress, damage, and cancer.
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Loss of the PTEN tumour suppressor leads to activation of the AKT kinases and increases the level of MDM2.
“Loss of the PTEN tumour suppressor leads to the activation of the AKT kinases and increases the level of MDM2 (Ref. 74).”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [74]
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- Authors
- Mayo, L. D., Dixon, J. E., Durden, D. L., Tonks, N. K., & Donner, D. B.
- Affiliations
- Indiana University Indianapolis (US)
- University of Michigan (US)
- Indiana University School of Medicine (US)
- Corresponding author
- Donner, David B.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-02
- Volume
- 277
- Issue
- 7
- Pages
- 5484-5489
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2132279561
- Cited by
- 351
- References
- 64
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 10 · 2021: 14 · 2020: 8 · 2019: 8 · 2018: 17 · 2017: 19 · 2016: 11 · 2015: 13 · 2014: 18 · 2013: 15 · 2012: 11
- FWCI
- 11.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- 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
- PTEN, p53, MDM2, tumor suppressor cooperation, glioblastoma, etoposide sensitivity, chemosensitization, PI3K/Akt signaling, nuclear translocation, cell cycle arrest, positive feedback loop, DNA damage response, U87 cells
- MeSH terms
- Cell Cycle, Cell Line, Cell Nucleus, Cloning, Molecular, Cytoplasm, DNA Damage, Dose-Response Relationship, Drug, Coloring Agents, Etoposide, Glioblastoma, Humans, Mutation, Neoplasms, Nuclear Proteins, Phosphoric Monoester Hydrolases, Precipitin Tests, Proto-Oncogene Proteins, Retroviridae, Tetrazolium Salts, Thiazoles, Transcription, Genetic, Transduction, Genetic, Tumor Cells, Cultured, Blotting, Western, Signal Transduction, Down-Regulation, Tumor Suppressor Protein p53, Genes, Reporter, Microscopy, Confocal, Tumor Suppressor Proteins, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-mdm2
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