p53 requires the stress sensor USF1 to direct appropriate cell fate decision

Simple item page
dc.contributor.authorBouafia, Amineen_ZA
dc.contributor.authorCorre, Sébastienen_ZA
dc.contributor.authorGilot, Daviden_ZA
dc.contributor.authorMouchet, Nicolasen_ZA
dc.contributor.authorPrince, Sharonen_ZA
dc.contributor.authorGalibert, Marie-Dominiqueen_ZA
dc.date.accessioned2016-01-11T06:55:40Z
dc.date.available2016-01-11T06:55:40Z
dc.date.issued2014en_ZA
dc.description.abstractGenomic instability is a major hallmark of cancer. To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs. The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) coordinates p53 function in making proper cell fate decisions. USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage. Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress. We further demonstrate that the loss of USF1 compromises p53 stability by enhancing p53-MDM2 complex formation and MDM2-mediated degradation of p53. In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents p53-MDM2 interaction. Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p53. These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage. They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway.en_ZA
dc.identifier.apacitationBouafia, A., Corre, S., Gilot, D., Mouchet, N., Prince, S., & Galibert, M. (2014). p53 requires the stress sensor USF1 to direct appropriate cell fate decision. <i>PLOS Genetics</i>, http://hdl.handle.net/11427/16300en_ZA
dc.identifier.chicagocitationBouafia, Amine, Sébastien Corre, David Gilot, Nicolas Mouchet, Sharon Prince, and Marie-Dominique Galibert "p53 requires the stress sensor USF1 to direct appropriate cell fate decision." <i>PLOS Genetics</i> (2014) http://hdl.handle.net/11427/16300en_ZA
dc.identifier.citationBouafia, A., Corre, S., Gilot, D., Mouchet, N., Prince, S., & Galibert, M. D. (2014). p53 requires the stress sensor USF1 to direct appropriate cell fate decision. PLoS Genet, 10(5), e1004309. doi:10.1371/journal.pgen.1004309en_ZA
dc.identifier.ris TY - Journal Article AU - Bouafia, Amine AU - Corre, Sébastien AU - Gilot, David AU - Mouchet, Nicolas AU - Prince, Sharon AU - Galibert, Marie-Dominique AB - Genomic instability is a major hallmark of cancer. To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs. The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) coordinates p53 function in making proper cell fate decisions. USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage. Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress. We further demonstrate that the loss of USF1 compromises p53 stability by enhancing p53-MDM2 complex formation and MDM2-mediated degradation of p53. In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents p53-MDM2 interaction. Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p53. These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage. They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway. DA - 2014 DB - OpenUCT DO - 10.1371/journal.pgen.1004309 DP - University of Cape Town J1 - PLOS Genetics LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - p53 requires the stress sensor USF1 to direct appropriate cell fate decision TI - p53 requires the stress sensor USF1 to direct appropriate cell fate decision UR - http://hdl.handle.net/11427/16300 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16300
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pgen.1004309
dc.identifier.vancouvercitationBouafia A, Corre S, Gilot D, Mouchet N, Prince S, Galibert M. p53 requires the stress sensor USF1 to direct appropriate cell fate decision. PLOS Genetics. 2014; http://hdl.handle.net/11427/16300.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDepartment of Human Biologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2014 Bouafia et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLOS Geneticsen_ZA
dc.source.urihttp://journals.plos.org/plosgeneticsen_ZA
dc.subject.otherUltraviolet Ben_ZA
dc.subject.otherDNA damageen_ZA
dc.subject.otherCell cycle and cell divisionen_ZA
dc.subject.otherCellular stress responsesen_ZA
dc.subject.otherTranscription factorsen_ZA
dc.subject.otherMelanoma cellsen_ZA
dc.subject.otherEnzyme-linked immunoassaysen_ZA
dc.subject.otherImmunoprecipitationen_ZA
dc.titlep53 requires the stress sensor USF1 to direct appropriate cell fate decisionen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Bouafia_p53_Requires_the_Stress_Sensor_USF1_2014.pdf
Size:
3.16 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Journal Articles