Meneghetti, BV and Wilson, R and Dias, CK and Cadore, NA and Klamt, F and Zaha, A and Ferreira, HB and Monteiro, KM, p53 mutants G245S and R337H associated with the Li-Fraumeni syndrome regulate distinct metabolic pathways, Biochimie, 198, (2022) pp. 141-154. ISSN 0300-9084 (2022) [Refereed Article]
Official URL: https://www.sciencedirect.com/science/article/pii/...
Li-Fraumeni and Li-Fraumeni-like syndromes (LFS/LFL) are hereditary cancer predisposition disorders associated with germline mutations in the TP53 tumor suppressor gene. Here, we stably expressed LFS/LFL-associated p53 mutants R337H and G245S in p53-null H1299 cells to study their cellular and molecular effects. Mutant proteins showed distinct oligomerization states and opposing effects on cell proliferation and viability. Stable expression of p53G245S enhanced cell proliferation and spheroid formation, while cells stably expressing p53R337H showed reduced proliferation and clonogenicity, along with increased cell death. Mass spectrometry analysis revealed that proteins whose expression was induced by p53R337H or p53G245S expression were related to distinct metabolic profiles. Proteins upregulated by p53G245S expression were associated with a Warburg phenotype, while proteins upregulated by p53R337H expression were related to oxidative phosphorylation and fatty acid oxidation. Differences in mitochondrial mass and activity between cells stably expressing p53R337H or p53G245S were further corroborated by High Resolution Respirometry, flow cytometry and qPCR assays. The implications of the different oncogenic properties of p53R337H and p53G245S on the clinical manifestation and treatment of LFS/LFL patients carrying these mutations are discussed.
|Item Type:||Refereed Article|
|Keywords:||proteomics, cancer biology, Li-Fraumeni syndrome|
|Research Division:||Biomedical and Clinical Sciences|
|Research Group:||Medical biochemistry and metabolomics|
|Research Field:||Medical biochemistry - proteins and peptides (incl. medical proteomics)|
|Objective Division:||Expanding Knowledge|
|Objective Group:||Expanding knowledge|
|Objective Field:||Expanding knowledge in the health sciences|
|UTAS Author:||Wilson, R (Dr Richard Wilson)|
|Web of Science® Times Cited:||1|
|Deposited By:||Central Science Laboratory|
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