Inactivation of p53 signaling by p73 or PTEN ablation results in a transformed phenotype that remains susceptible to Nutlin-3 mediated apoptosis
Open accessAbstract
The p53 signaling pathway is frequently disrupted in carcinogenesis. However, roughly 50% of all cancers express wild-type p53 and have alterations in accessory signaling components required for p53 activity. Using the well described E1A/RAS transformation model, in which p53 activity must be suppressed for transformation, we show here that p53 is inactive and unable to suppress transformation following ablation of p73 or PTEN. However, despite the transformed phenotype conferred by p53 inactivation following p73 or PTEN loss, p53 could be fully activated by Nutlin-3, resulting in efficient caspase-mediated apoptosis. Our novel and unexpected finding provides important information regarding the efficacy of Nutlin-3 and indicates that patients with tumors deficient in p53 function due to p73 or PTEN loss may benefit from Nutlin-3 treatment.
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Although AKT has multiple downstream targets in addition to MDM2, tumour cells with activated AKT pathways are sensitive to MDM2 antagonists.
“Although AKT has multiple downstream targets in addition to MDM2, tumour cells with activated AKT pathways are sensitive to MDM2 antagonists75,76.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [75]
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MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · see citing works
- Authors
- Cipriano, R., Patton, J. T., Mayo, L. D., & Jackson, M. W.
- Affiliations
- Case Western Reserve University (US)
- Case Comprehensive Cancer Center (US)
- Corresponding author
- Jackson, Mark W.
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2010-04
- Volume
- 9
- Issue
- 7
- Pages
- 1373-1379
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2053601921
- Cited by
- 20
- References
- 0
- Citations by year
- 2025: 1 · 2023: 3 · 2021: 2 · 2020: 1 · 2017: 3 · 2013: 3 · 2012: 4
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Case Western Reserve University
- Université de Genève
- National Institutes of Health
- National Cancer Institute (R01CA109262)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- p53 pathway, p73, PTEN, Nutlin-3, MDM2 inhibition, apoptosis, caspase activation, tumor suppression, p53 reactivation, cancer therapy
- MeSH terms
- Tumor Protein p73, Cell Line, DNA-Binding Proteins, Humans, Imidazoles, Nuclear Proteins, Piperazines, Blotting, Western, Tumor Suppressor Protein p53, Apoptosis, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-mdm2
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