Department of Cell and Developmental Biology; Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
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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Citation: 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
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Carr, Michael I.; Roderick, Justine E.; Gannon, Hugh S.; Kelliher, Michelle A.; and Jones, Stephen N., "Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis" (2016). Cell and Developmental Biology Publications and Presentations. 194.
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