Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
| العنوان: | Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death |
|---|---|
| المؤلفون: | Joshua H. Choe, Tatsuya Kawase, An Xu, Asja Guzman, Aleksandar Z. Obradovic, Ana Maria Low-Calle, Bita Alaghebandan, Ananya Raghavan, Kaitlin Long, Paul M. Hwang, Joshua D. Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol Prives |
| المصدر: | Cancer Discovery. 13:1250-1273 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Oncology |
| الوصف: | Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li–Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein. Significance: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches. See related commentary by Stieg et al., p. 1046. See related article by Gencel-Augusto et al., p. 1230. This article is highlighted in the In This Issue feature, p. 1027 |
| تدمد: | 2159-8290 2159-8274 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::ee3f5faba37fa6f65003b502bf802e04 https://doi.org/10.1158/2159-8290.cd-22-0882 |
| رقم الأكسشن: | edsair.doi...........ee3f5faba37fa6f65003b502bf802e04 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21598290 21598274 |
|---|