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Article: The E3 ubiquitin ligase mule acts through the ATM-p53 axis to maintain b lymphocyte homeostasis

TitleThe E3 ubiquitin ligase mule acts through the ATM-p53 axis to maintain b lymphocyte homeostasis
Authors
Issue Date2012
Citation
Journal of Experimental Medicine, 2012, v. 209, n. 1, p. 173-186 How to Cite?
AbstractCellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) is an E3 ubiquitin ligase that targets the proapoptotic molecule p53 for polyubiquitination and degradation. To elucidate the role of Mule in B lymphocyte homeostasis, B cell-specific Mule knockout (BMKO) mice were generated using the Cre- LoxP recombination system. Analysis of BMKO mice showed that Mule was essential for B cell development, proliferation, homeostasis, and humoral immune responses. p53 transactivation was increased by two- to fourfold in Mule-deficient B cells at steady state. Genetic ablation of p53 in BMKO mice restored B cell development, proliferation, and homeostasis. p53 protein was increased in resting Mule-deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells. Loss of Mule in both MEFs and B cells at steady state resulted in increased levels of phospho-ataxia telangiectasia mutated (ATM) and the ATM substrate p53. Under genotoxic stress, BMKO B cells were resistant to apoptosis, and control MEFs exhibited evidence of a physical interaction between Mule and phospho-ATM. Phospho-ATM, phospho-p53, and Brca1 levels were reduced in Muledeficient B cells and MEFs subjected to genotoxic stress. Thus, Mule regulates the ATM- p53 axis to maintain B cell homeostasis under both steady-state and stress conditions.
Persistent Identifierhttp://hdl.handle.net/10722/292711
ISSN
2020 Impact Factor: 14.307
2020 SCImago Journal Rankings: 8.483
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHao, Zhenyue-
dc.contributor.authorDuncan, Gordon S.-
dc.contributor.authorSu, Yu Wen-
dc.contributor.authorLi, Wanda Y.-
dc.contributor.authorSilvester, Jennifer-
dc.contributor.authorHong, Claire-
dc.contributor.authorYou, Han-
dc.contributor.authorBrenner, Dirk-
dc.contributor.authorGorrini, Chiara-
dc.contributor.authorHaight, Jillian-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorYou-Ten, Annick-
dc.contributor.authorMcCracken, Susan-
dc.contributor.authorElia, Andrew-
dc.contributor.authorLi, Qinxi-
dc.contributor.authorDetmar, Jacqui-
dc.contributor.authorJurisicova, Andrea-
dc.contributor.authorHobeika, Elias-
dc.contributor.authorReth, Michael-
dc.contributor.authorSheng, Yi-
dc.contributor.authorLang, Philipp A.-
dc.contributor.authorOhashi, Pamela S.-
dc.contributor.authorZhong, Qing-
dc.contributor.authorWang, Xiaodong-
dc.contributor.authorMak, Tak W.-
dc.date.accessioned2020-11-17T14:57:03Z-
dc.date.available2020-11-17T14:57:03Z-
dc.date.issued2012-
dc.identifier.citationJournal of Experimental Medicine, 2012, v. 209, n. 1, p. 173-186-
dc.identifier.issn0022-1007-
dc.identifier.urihttp://hdl.handle.net/10722/292711-
dc.description.abstractCellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) is an E3 ubiquitin ligase that targets the proapoptotic molecule p53 for polyubiquitination and degradation. To elucidate the role of Mule in B lymphocyte homeostasis, B cell-specific Mule knockout (BMKO) mice were generated using the Cre- LoxP recombination system. Analysis of BMKO mice showed that Mule was essential for B cell development, proliferation, homeostasis, and humoral immune responses. p53 transactivation was increased by two- to fourfold in Mule-deficient B cells at steady state. Genetic ablation of p53 in BMKO mice restored B cell development, proliferation, and homeostasis. p53 protein was increased in resting Mule-deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells. Loss of Mule in both MEFs and B cells at steady state resulted in increased levels of phospho-ataxia telangiectasia mutated (ATM) and the ATM substrate p53. Under genotoxic stress, BMKO B cells were resistant to apoptosis, and control MEFs exhibited evidence of a physical interaction between Mule and phospho-ATM. Phospho-ATM, phospho-p53, and Brca1 levels were reduced in Muledeficient B cells and MEFs subjected to genotoxic stress. Thus, Mule regulates the ATM- p53 axis to maintain B cell homeostasis under both steady-state and stress conditions.-
dc.languageeng-
dc.relation.ispartofJournal of Experimental Medicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleThe E3 ubiquitin ligase mule acts through the ATM-p53 axis to maintain b lymphocyte homeostasis-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1084/jem.20111363-
dc.identifier.pmid22213803-
dc.identifier.pmcidPMC3260869-
dc.identifier.scopuseid_2-s2.0-84863116292-
dc.identifier.volume209-
dc.identifier.issue1-
dc.identifier.spage173-
dc.identifier.epage186-
dc.identifier.eissn1540-9538-
dc.identifier.isiWOS:000299820200014-
dc.identifier.issnl0022-1007-

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