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dc.contributor.authorCarr, Michael I.
dc.contributor.authorRoderick, Justine E.
dc.contributor.authorGannon, Hugh S.
dc.contributor.authorKelliher, Michelle A.
dc.contributor.authorJones, Stephen N.
dc.date2022-08-11T08:08:03.000
dc.date.accessioned2022-08-23T15:40:55Z
dc.date.available2022-08-23T15:40:55Z
dc.date.issued2016-09-06
dc.date.submitted2016-09-19
dc.identifier.citation<p>Cell Rep. 2016 Sep 6;16(10):2618-29. doi: 10.1016/j.celrep.2016.08.014. Epub 2016 Aug 25. <a href="http://dx.doi.org/10.1016/j.celrep.2016.08.014">Link to article on publisher's site</a></p>
dc.identifier.issn2211-1247 (Electronic)
dc.identifier.doi10.1016/j.celrep.2016.08.014
dc.identifier.pmid27568562
dc.identifier.urihttp://hdl.handle.net/20.500.14038/26508
dc.description.abstractATM 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=27568562&dopt=Abstract">Link to Article in PubMed</a>
dc.rights<p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</p>
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCancer Biology
dc.subjectCell Biology
dc.titleMdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis
dc.typeJournal Article
dc.source.journaltitleCell reports
dc.source.volume16
dc.source.issue10
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1193&amp;context=cellbiology_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/cellbiology_pp/194
dc.identifier.contextkey9135200
refterms.dateFOA2022-08-23T15:40:55Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathcellbiology_pp/194
dc.contributor.departmentUMass Metabolic Network
dc.contributor.departmentDepartment of Molecular, Cell and Cancer Biology
dc.contributor.departmentDepartment of Cell and Developmental Biology
dc.source.pages2618-29


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<p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</p>
Except where otherwise noted, this item's license is described as <p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</p>