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Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization
Open accessAbstract
Establishment of primary mouse embryo fibroblasts (MEFs) as continuously growing cell lines is normally accompanied by loss of the p53 or p19(ARF) tumor suppressors, which act in a common biochemical pathway. myc rapidly activates ARF and p53 gene expression in primary MEFs and triggers replicative crisis by inducing apoptosis. MEFs that survive myc overexpression sustain p53 mutation or ARF loss during the process of establishment and become immortal. MEFs lacking ARF or p53 exhibit an attenuated apoptotic response to myc ab initio and rapidly give rise to cell lines that proliferate in chemically defined medium lacking serum. Therefore, ARF regulates a p53-dependent checkpoint that safeguards cells against hyperproliferative, oncogenic signals.
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“p19 Arf has been shown to inhibit Mdm2-mediated degradation of p53 (19-21) and is clearly required for activation of p53 in response to aberrant cell cycle entry (19) and oncogene activation (22-24).”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [22]
Experimental — accuracy not yet measuredIn the citing paper
“However, under stressful conditions, such as when oncogenes are activated, loss of Arf results in deregulated Mdm2 and the inability of a cell to effectively activate p53 (Eischen, et al., 1999; Schmitt, et al., 1999; Zindy, et al., 1998).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Zindy, et al., 1998
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Metadata
- Authors
- Zindy, F., Eischen, C. M., Randle, D. H., Kamijo, T., Cleveland, J. L., Sherr, C. J., & Roussel, M. F.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1998-08-01
- Volume
- 12
- Issue
- 15
- Pages
- 2424-2433
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC317045
- OpenAlex
- W2046958356
- Cited by
- 1,245
- References
- 60
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 14 · 2023: 32 · 2022: 10 · 2021: 27 · 2020: 15 · 2019: 22 · 2018: 15 · 2017: 23 · 2016: 28 · 2015: 19 · 2014: 43 · 2013: 45 · 2012: 46
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- St. Jude Children's Research Hospital (CA21765)
- American Lebanese Syrian Associated Charities (CA 21765)
- National Institutes of Health (5r01ca056819-08, CA21765))
- National Cancer Institute (CA-71907, CA56819, P30CA021765, P01CA071907)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 44158, R01DK044158)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- MYC signaling, ARF tumor suppressor, p53, apoptosis, cell immortalization, p19ARF, TP53 mutation, oncogenic transformation
- MeSH terms
- Animals, Cell Division, Cell Line, Humans, Models, Biological, Mutation, Proteins, Signal Transduction, Gene Expression, Genes, Tumor Suppressor, Genes, p53, Genes, myc, Apoptosis, Gene Deletion, Tumor Suppressor Protein p14ARF, Mice
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