دورية أكاديمية
أعرض في EDS

Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells.

التفاصيل البيبلوغرافية
العنوان: Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells.
المؤلفون: Wang Z; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Burigotto M; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy., Ghetti S; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy., Vaillant F; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Tan T; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Capaldo BD; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Palmieri M; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Hirokawa Y; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Tai L; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia., Simpson DS; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Chang C; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia., Huang AS; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Lieschke E; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Diepstraten ST; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Kaloni D; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Riffkin C; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia., Huang DCS; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Li Wai Suen CSN; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Garnham AL; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Gibbs P; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Visvader JE; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Sieber OM; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Herold MJ; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Fava LL; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy., Kelly GL; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia., Strasser A; The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
المصدر: Cancer discovery [Cancer Discov] 2024 Feb 08; Vol. 14 (2), pp. 362-379.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Philadelphia, PA : American Association for Cancer Research
مواضيع طبية MeSH: Tumor Suppressor Protein p53*/genetics , Tumor Suppressor Protein p53*/metabolism , Colonic Neoplasms*/genetics, Humans ; Mice ; Animals ; Cell Line, Tumor ; Mutation ; Cell Proliferation
مستخلص: 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.
(©2023 The Authors; Published by the American Association for Cancer Research.)
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معلومات مُعتمدة: 101671 United Kingdom WT_ Wellcome Trust
المشرفين على المادة: 0 (Tumor Suppressor Protein p53)
0 (TP53 protein, human)
تواريخ الأحداث: Date Created: 20231025 Date Completed: 20240209 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC10850947
DOI: 10.1158/2159-8290.CD-23-0402
PMID: 37877779
قاعدة البيانات: MEDLINE
الوصف
تدمد:2159-8290
DOI:10.1158/2159-8290.CD-23-0402