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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss
Tamara Terzian1, Young-Ah Suh, Tomoo Iwakuma
1Department of Cancer Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
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 p16INK4a, a member of the Rb tumor suppressor pathway. Mice lacking Mdm2 or p16INK4a 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.
Insights
Mutant p53 stabilization is essential for its cancer-promoting gain-of-function. Targeting wild-type p53 may inadvertently stabilize mutant p53, worsening cancer outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p53 tumor suppressor is frequently inactivated by missense mutations in human cancers.
- Understanding the regulation of mutant p53 stability is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the regulatory mechanisms controlling mutant p53 stability.
- To determine the role of mutant p53 stability in tumor progression and gain-of-function phenotypes.
Main Methods:
- Generation of mice with a specific p53 missense mutation (p53R172H) mimicking human cancer mutations.
- Examination of mutant p53 stability in relation to Mdm2 (an E3 ubiquitin ligase) and p16INK4a (a component of the Rb pathway).
- Analysis of tumor onset, metastasis, and Rb pathway integrity in genetically modified mice.
Main Results:
- Mice lacking Mdm2 or p16INK4a exhibited stabilized mutant p53, earlier tumor onset, and a metastatic phenotype.
- Tumors with stable mutant p53 showed defects in the Rb pathway.
- Ionizing radiation was found to stabilize both wild-type and mutant p53.
Conclusions:
- Mutant p53 stabilization is a prerequisite for its gain-of-function activity, including promoting metastasis.
- Therapeutic strategies targeting wild-type p53 activation may unexpectedly stabilize mutant p53, potentially exacerbating cancer progression.
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