Inactivation of Mdm2 restores apoptosis proficiency of cooperativity mutant p53 in vivo
| العنوان: | Inactivation of Mdm2 restores apoptosis proficiency of cooperativity mutant p53 in vivo |
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| المؤلفون: | Thorsten Stiewe, Boris Klimovich, Oleg Timofeev |
| المصدر: | Cell Cycle |
| بيانات النشر: | Informa UK Limited, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Cyclin-Dependent Kinase Inhibitor p21, 0301 basic medicine, Senescence, Programmed cell death, Cell cycle checkpoint, Mutant, Apoptosis, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Puma, Animals, Molecular Biology, biology, Homozygote, Proto-Oncogene Proteins c-mdm2, Cell Biology, Embryo, Mammalian, biology.organism_classification, Cell biology, 030104 developmental biology, 030220 oncology & carcinogenesis, Embryo Loss, biology.protein, Mdm2, Mutant Proteins, Tumor Suppressor Protein p53, Gene Deletion, Research Paper, Developmental Biology |
| الوصف: | TP53 mutations are found in 50% of all cancers and mutated TP53 status is considered poor for treatment. However, some TP53 mutations exhibit only partial loss-of-function (LOF), meaning they retain residual transcriptional and non-transcriptional activities that are potentially beneficial for therapy. Earlier we have characterized a knock-in mouse model for the partial LOF mutant Trp53(E177R) (p53RR). Reduced DNA binding cooperativity of this mutant led to the loss of p53-dependent apoptosis, while p53 functions in cell cycle control, senescence, metabolism, and antioxidant defense remained intact. Concomitantly, tumor suppression was evident but strongly compromised compared to wild-type mice. Here we used the Trp53(E177R) mouse as a model to investigate whether residual functions of mutant p53 can be engaged to induce cell death, which is considered the most desirable outcome of tumor therapy. We made use of Mdm2 knock-out in developing embryos as a sensitive tool for detecting remaining p53 activities. Genetic ablation of Mdm2 led to embryonic lethality in Trp53(E177R/E177R) homozygotes at days 9.5–11.5. This effect was not rescued by concomitant p21-knockout, indicating its independence of p21-mediated cell cycle arrest. Instead, immunohistochemical analysis showed widespread apoptosis in tissues of defective embryos accompanied by persistent accumulation of p53RR protein. This led to partial restoration of the mutant’s proficiency in transcriptional induction of the pro-apoptotic genes Bbc3 (Puma) and Bax. These data indicate that increased quantity can compensate for qualitative defects of p53 mutants and suggest that Mdm2-targeting (potentially in combination with other drugs) might be effective against cells bearing p53 partial LOF mutants. |
| تدمد: | 1551-4005 1538-4101 |
| DOI: | 10.1080/15384101.2019.1693748 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::964a06f351145d6dec9f423afecf8a97 https://doi.org/10.1080/15384101.2019.1693748 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....964a06f351145d6dec9f423afecf8a97 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15514005 15384101 |
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| DOI: | 10.1080/15384101.2019.1693748 |