A novel PTEN/mutant p53/c-Myc/Bcl-XL axis mediates context-dependent oncogenic effects of PTEN with implications for cancer prognosis and therapy
Open accessAbstract
Phosphatase and tensin homolog located on chromosome 10 (PTEN) is one of the most frequently mutated tumor suppressors in human cancer including in glioblastoma. Here, we show that PTEN exerts unconventional oncogenic effects in glioblastoma through a novel PTEN/mutant p53/c-Myc/Bcl-XL molecular and functional axis. Using a wide array of molecular, genetic, and functional approaches, we demonstrate that PTEN enhances a transcriptional complex containing gain-of-function mutant p53, CBP, and NFY in human glioblastoma cells and tumor tissues. The mutant p53/CBP/NFY complex transcriptionally activates the oncogenes c-Myc and Bcl-XL, leading to increased cell proliferation, survival, invasion, and clonogenicity. Disruption of the mutant p53/c-Myc/Bcl-XL axis or mutant p53/CBP/NFY complex reverses the transcriptional and oncogenic effects of PTEN and unmasks its tumor-suppressive function. Consistent with these data, we find that PTEN expression is associated with worse patient survival than PTEN loss in tumors harboring mutant p53 and that a small molecule modulator of p53 exerts greater antitumor effects in PTEN-expressing cancer cells. Altogether, our study describes a new signaling pathway that mediates context-dependent oncogenic/tumor-suppressive role of PTEN. The data also indicate that the combined mutational status of PTEN and p53 influences cancer prognosis and anticancer therapies that target PTEN and p53.
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PTEN, GOF mut-p53, CBP and NF-ɣ form a transcriptional complex in human glioblastoma tumor samples.
“Moreover, PTEN, GOF mut-p53, CBP and NF-ɣ form a transcriptional complex in human GBM tumor samples.”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [107]
The section on the mut-p53/CBP/NFYA complex reports that it exists in human glioblastoma tumor specimens. The section on PTEN regulation says PTEN interacts with mut-p53 and CBP and enhances their association with NFYA in glioblastoma cells, but does not show that PTEN is a fourth component of the complex in tumor samples. The paper calls the factor NFYA, rather than “NF-ɣ.” (LLM, conf=0.89)
Experimental — accuracy not yet measuredInhibition of mut-p53 with PRIMA-1 exhibited greater antitumor effects in samples expressing PTEN.
“Inhibition of mut-p53 with the small molecule PRIMA-1 exhibited greater antitumor effects in samples expressing PTEN, emphasizing their tumor promoting interaction [107].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [107]
Molecular targets of the PTEN/GOF mut-p53/CBP/NF-ɣ complex include the oncogenes c-Myc and Bcl-XL.
“Molecular targets of this complex include the oncogenes c-Myc and Bcl-XL.”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [107]
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The p53 Pathway in Glioblastoma
Zhang, Y., Dube, C., Gibert, M., Cruickshanks, N., Wang, B., Coughlan, M., Yang, Y., Setiady, I., Deveau, C., Saoud, K., et al. (2018) · Cancers · doi:10.3390/cancers10090297 · Cited by 440 · see citing works
Self-citation
- Authors
- Huang, X., Zhang, Y., Tang, Y., Butler, N., Kim, J., Guessous, F., Schiff, D., Mandell, J., & Abounader, R.
- Affiliations
- University of Virginia (US)
- University of Virginia Cancer Center (US)
- Corresponding author
- Abounader, Roger
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 15
- Issue
- 8
- Pages
- 952-965
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC3730046
- OpenAlex
- W1518297150
- Cited by
- 53
- References
- 42
- Citations by year
- 2026: 3 · 2024: 1 · 2023: 7 · 2022: 1 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 7 · 2015: 6 · 2014: 4 · 2013: 2
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA134843, P30CA044579)
- National Institute of Neurological Disorders and Stroke (R01NS045209)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- PTEN, mutant p53, c-Myc, Bcl-xL, CBP, NF-Y, glioblastoma, transcriptional activation, cancer prognosis, tumor invasion, cell proliferation
- MeSH terms
- Glioblastoma, Humans, Mutation, Peptide Fragments, Prognosis, Promoter Regions, Genetic, Protein Binding, Sialoglycoproteins, Tumor Cells, Cultured, Immunoblotting, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Apoptosis, CCAAT-Binding Factor, RNA Interference, Cell Line, Tumor, Chromatin Immunoprecipitation, Cell Proliferation, bcl-X Protein, PTEN Phosphohydrolase, HEK293 Cells
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