PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations
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Abstract
We show, for the first time, that the tumor suppressor PTEN can have tumor-promoting properties. We show that PTEN acquires these unexpected properties by enhancing gain-of-function mutant p53 (mut-p53) protein levels. We find that PTEN restoration to cells harboring mut-p53 leads to induction of G1-S cell cycle progression and cell proliferation and to inhibition of cell death. Conversely, PTEN inhibition in cells expressing wild-type PTEN and mut-p53 leads to inhibition of cell proliferation and inhibition of in vivo tumor growth. We show the dependency of the tumor-promoting effects of PTEN on mut-p53 by showing that knockdown of mut-p53 expression inhibits or reverses the tumor-promoting effects of PTEN. Mechanistically, we show that PTEN expression enhances mut-p53 protein levels via inhibition of mut-p53 degradation by Mdm2 and possibly also via direct protein binding. These findings describe a novel function of PTEN and have important implications for experimental and therapeutic strategies that aim at manipulating PTEN or p53 in human tumors. They suggest that the mutational status of PTEN and p53 should be considered to achieve favorable therapeutic outcomes. The findings also provide an explanation for the low frequency of simultaneous mutations of PTEN and p53 in human cancer. [Cancer Res 2008;68(6):1723–31]
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PTEN regulates GOF mut-p53 expression through inhibition of MDM2-mediated degradation and possibly also through direct protein interaction.
“This novel function is a result of PTEN regulating GOF mut-p53 expression through the inhibition of MDM2-mediated degradation and possibly also through direct protein interaction [106].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [106]
PTEN displays aberrant tumor-promoting activity in glioblastoma cell lines.
“Our group has shown that PTEN, another major tumor suppressor, displays aberrant tumor-promoting activity in GBM cell lines.”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [106]
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- Authors
- Li, Y., Guessous, F., Kwon, S., Kumar, M., Ibidapo, O., Fuller, L., Johnson, E., Lal, B., Hussaini, I., Bao, Y., Laterra, J., Schiff, D., & Abounader, R.
- Affiliations
- 1Neurology, Departments of
- Johns Hopkins University (US)
- University of Virginia (US)
- 2Microbiology, and
- ORCID
- Venue
- Cancer Research
- Published
- 2008-03-13
- Volume
- 68
- Issue
- 6
- Pages
- 1723-1731
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3813002
- OpenAlex
- W2092777351
- Cited by
- 95
- References
- 40
- Citations by year
- 2025: 6 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 2 · 2016: 6 · 2015: 3 · 2014: 9 · 2013: 8 · 2012: 3
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS045209, R01NS032148)
- 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 › Protein Tyrosine Phosphatases
- Keywords
- PTEN, p53 gain-of-function mutation, tumor promotion, tumor suppressor function, MDM2, p53 degradation, G1/S cell cycle progression, cell proliferation, apoptosis inhibition, tumor growth, cancer therapy
- MeSH terms
- Cell Cycle, Glioblastoma, Humans, Mutation, Transfection, Tumor Suppressor Protein p53, Cell Death, RNA, Small Interfering, Cell Line, Tumor, Cell Growth Processes, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-mdm2
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