Department of Cell and Developmental Biology; Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Cancer Biology | Cell Biology
ATM phosphorylation of Mdm2-S394 is required for robust p53 stabilization and activation in DNA-damaged cells. We have now utilized Mdm2(S394A) knockin mice to determine that phosphorylation of Mdm2-S394 regulates p53 activity and the DNA damage response in lymphatic tissues in vivo by modulating Mdm2 stability. Mdm2-S394 phosphorylation delays lymphomagenesis in Emu-myc transgenic mice, and preventing Mdm2-S394 phosphorylation obviates the need for p53 mutation in Myc-driven tumorigenesis. However, irradiated Mdm2(S394A) mice also have increased hematopoietic stem and progenitor cell functions, and we observed decreased lymphomagenesis in sub-lethally irradiated Mdm2(S394A) mice. These findings document contrasting effects of ATM-Mdm2 signaling on p53 tumor suppression and reveal that destabilizing Mdm2 by promoting its phosphorylation by ATM would be effective in treating oncogene-induced malignancies, while inhibiting Mdm2-S394 phosphorylation during radiation exposure or chemotherapy would ameliorate bone marrow failure and prevent the development of secondary hematological malignancies.
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DOI of Published Version
Cell Rep. 2016 Sep 6;16(10):2618-29. doi: 10.1016/j.celrep.2016.08.014. Epub 2016 Aug 25. Link to article on publisher's site
Carr MI, Roderick JE, Gannon HS, Kelliher MA, Jones SN. (2016). Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis. Cell and Developmental Biology Publications. https://doi.org/10.1016/j.celrep.2016.08.014. Retrieved from https://escholarship.umassmed.edu/cellbiology_pp/194
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