The DOI matches its Crossref record; 18 of the 18 references it cites were found in a registry or an index.
The inherent instability of mutant p53 is alleviated by Mdm2 or p16 INK4a loss
Open accessAbstract
The p53 tumor suppressor is often disrupted in human cancers by the acquisition of missense mutations. We generated mice with a missense mutation at codon 172 that mimics the p53R175H hot spot mutation in human cancer. p53 homozygous mutant mice have unstable mutant p53 in normal cells and stabilize mutant p53 in some but not all tumors. To investigate the significance of these data, we examined the regulation of mutant p53 stability by Mdm2, an E3 ubiquitin ligase that targets p53 for degradation, and p16 INK4a , a member of the Rb tumor suppressor pathway. Mice lacking Mdm2 or p16 INK4a stabilized mutant p53, and revealed an earlier age of tumor onset than p53 mutant mice and a gain-of-function metastatic phenotype. Analysis of tumors from p53 homozygous mutant mice with stable p53 revealed defects in the Rb pathway. Additionally, ionizing radiation stabilizes wild-type and mutant p53. Thus, the stabilization of mutant p53 is not a given but it is a prerequisite for its gain-of-function phenotype. Since mutant p53 stability mimics that of wild-type p53, these data indicate that drugs aimed at activating wild-type p53 will also stabilize mutant p53 with dire consequences.
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“in many situations, missense mutant p53 is expressed at high levels in tumor cells, partly due to the inability of mutant p53 to induce gene expression of MDM2,379”
From Targeting p53 pathways: mechanisms, structures, and advances in therapy (2023) · cites this paper as [379]
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Cites
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218 · cited 1×
“Oncogenic signals such as activating Ras mutations or increased c-Myc expression also stabilize p53 in normal cells and result in senescence or apoptosis, respectively (Hermeking and Eick 1994; Wagner et al. 1994; Serrano et al. 1997; Ferbeyre et al. 2002).”
BackgroundMdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · cited 2×
“Mdm2, a negative regulator of p53, is an E3 ubiquitin ligase that targets wild-type p53 for degradation (Haupt et al. 1997; Honda et al. 1997; Kubbutat et al. 1997).”
BackgroundA cell cycle regulator potentially involved in genesis of many tumor types
Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S. V., Stockert, E., Day, R. S., Johnson, B. E., & Skolnick, M. H. (1994) · Science · doi:10.1126/science.8153634 · Cited by 2,751 · cited 1×
“Lastly, p16 loss, a common event in human cancers (Kamb et al. 1994; Nobori et al. 1994), also stabilized mutant p53 in vivo and yielded a metastatic phenotype.”
BackgroundDNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
Shieh, S.-Y., Ikeda, M., Taya, Y., & Prives, C. (1997) · Cell · doi:10.1016/s0092-8674(00)80416-x · Cited by 2,100
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951
The RB and p53 pathways in cancer
Sherr, C. J., & McCormick, F. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00102-2 · Cited by 1,690
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Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
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Cited by
Muller, P. A. J., & Vousden, K. H. (2013) · Nature Cell Biology · doi:10.1038/ncb2641 · Cited by 1,647
When mutants gain new powers: News from the mutant p53 field
Brosh, R., & Rotter, V. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2693 · Cited by 1,132
Rivlin, N., Brosh, R., Oren, M., & Rotter, V. (2011) · Genes & Cancer · doi:10.1177/1947601911408889 · Cited by 1,033
Targeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016
Targeting mutant p53 for efficient cancer therapy
Bykov, V. J. N., Eriksson, S. E., Bianchi, J., & Wiman, K. G. (2018) · Nature Reviews Cancer · doi:10.1038/nrc.2017.109 · Cited by 889
Metadata
- Authors
- Terzian, T., Suh, Y.-A., Iwakuma, T., Post, S. M., Neumann, M., Lang, G. A., Van Pelt, C. S., & Lozano, G.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-05-15
- Volume
- 22
- Issue
- 10
- Pages
- 1337-1344
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2098098349
- Cited by
- 357
- References
- 18
- Type
- posted content
- Language
- en
- Open access
- diamond
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- Terzian, T., Suh, Y.-A., Iwakuma, T., Post, S. M., Neumann, M., Lang, G. A., Van Pelt, C. S., & Lozano, G. (2008). The inherent instability of mutant p53 is alleviated by Mdm2 or p16 INK4a loss. Genes & Development. https://doi.org/10.1101/gad.1662908
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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