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Updated: Jul 12, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and
Zilu Wang1,2, Matteo Burigotto3, Sabrina Ghetti3
1The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.
Abstract:
Mutations in the tumor suppressor TP53 cause cancer and impart poor chemotherapeutic responses, reportedly through loss-of-function, dominant-negative effects and gain-of-function (GOF) activities. The relative contributions of these attributes is unknown. We found that removal of 12 different TP53 mutants with reported GOFs by CRISPR/Cas9 did not impact proliferation and response to chemotherapeutics of 15 human cancer cell lines and colon cancer-derived organoids in culture. Moreover, removal of mutant TP53/TRP53 did not impair growth or metastasis of human cancers in immune-deficient mice or growth of murine cancers in immune-competent mice. DepMap mining revealed that removal of 158 different TP53 mutants had no impact on the growth of 391 human cancer cell lines. In contrast, CRISPR-mediated restoration of wild-type TP53 extinguished the growth of human cancer cells in vitro. These findings demonstrate that LOF but not GOF effects of mutant TP53/TRP53 are critical to sustain expansion of many tumor types.
Significance:
This study provides evidence that removal of mutant TP53, thereby deleting its reported GOF activities, does not impact the survival, proliferation, metastasis, or chemotherapy responses of cancer cells. Thus, approaches that abrogate expression of mutant TP53 or target its reported GOF activities are unlikely to exert therapeutic impact in cancer. See related commentary by Lane, p. 211 . This article is featured in Selected Articles from This Issue, p. 201.
Insights
Loss of TP53 gain-of-function (GOF) activity did not affect cancer cell proliferation or treatment response. Only restoring wild-type TP53 function suppressed tumor growth, indicating loss-of-function (LOF) is key in many cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Mutations in the tumor suppressor TP53 are common in cancer, leading to loss-of-function (LOF), dominant-negative, and gain-of-function (GOF) effects.
- The specific contribution of each mutation type to cancer progression and treatment resistance remains unclear.
Purpose of the Study:
- To investigate the role of TP53 gain-of-function (GOF) activities in cancer cell proliferation, chemotherapy response, and tumor growth.
- To determine whether targeting TP53 GOF is a viable therapeutic strategy.
Main Methods:
- CRISPR/Cas9 gene editing was used to remove various TP53 mutants with reported GOF activities from human cancer cell lines and organoids.
- The impact of TP53 mutant removal on cancer cell proliferation, response to chemotherapeutics, tumor growth, and metastasis was assessed in vitro and in vivo (using immune-deficient and immune-competent mouse models).
- DepMap database was mined to analyze the effect of TP53 mutant removal on a large set of human cancer cell lines.
Main Results:
- Removal of TP53 mutants with reported GOF activities did not affect the proliferation or chemotherapeutic response of cancer cell lines and organoids.
- Eliminating mutant TP53 did not impair tumor growth or metastasis in mouse models.
- Analysis of 391 human cancer cell lines revealed that removing 158 different TP53 mutants had no impact on cell growth.
- Conversely, restoring wild-type TP53 function significantly inhibited human cancer cell growth in vitro.
Conclusions:
- The gain-of-function (GOF) activities of mutant TP53 are not critical for the sustained growth of many tumor types.
- Loss-of-function (LOF) of TP53 is the primary driver for tumor expansion in many cancers.
- Therapeutic strategies targeting mutant TP53 GOF are unlikely to be effective in treating cancer.
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