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dc.contributor.authorOrgaz, JL
dc.contributor.authorCrosas-Molist, E
dc.contributor.authorSadok, A
dc.contributor.authorPerdrix-Rosell, A
dc.contributor.authorMaiques, O
dc.contributor.authorRodriguez-Hernandez, I
dc.contributor.authorMonger, J
dc.contributor.authorMele, S
dc.contributor.authorGeorgouli, M
dc.contributor.authorBridgeman, V
dc.contributor.authorKaragiannis, P
dc.contributor.authorLee, Rebecca J
dc.contributor.authorPandya, P
dc.contributor.authorBoehme, L
dc.contributor.authorWallberg, F
dc.contributor.authorTape, C
dc.contributor.authorKaragiannis, SN
dc.contributor.authorMalanchi, I
dc.contributor.authorSanz-Moreno, V
dc.date.accessioned2020-02-27T16:55:24Z
dc.date.available2020-02-27T16:55:24Z
dc.date.issued2020en
dc.identifier.citationMorgan RD, Banerjee S, Hall M, Clamp AR, Zhou C, Hasan J, et al. Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial. Gynecol Oncol. 2020.en
dc.identifier.pmid31935375en
dc.identifier.doi10.1016/j.ccell.2019.12.003en
dc.identifier.urihttp://hdl.handle.net/10541/622757
dc.description.abstractBACKGROUND & AIMS: Activation factor-1 transcription factor family members activating transcription factors 2 and 7 (ATF2 and ATF7) have highly redundant functions owing to highly homologous DNA binding sites. Their role in intestinal epithelial homeostasis and repair is unknown. Here, we assessed the role of these proteins in these conditions in an intestine-specific mouse model. METHODS: We performed in vivo and ex vivo experiments using Villin-CreERT2Atf2fl/flAtf7ko/ko mice. We investigated the effects of intestinal epithelium-specific deletion of the Atf2 DNA binding region in Atf7-/- mice on cellular proliferation, differentiation, apoptosis, and epithelial barrier function under homeostatic conditions. Subsequently, we exposed mice to 2% dextran sulfate sodium (DSS) for 7 days and 12 Gy whole-body irradiation and assessed the response to epithelial damage. RESULTS: Activating phosphorylation of ATF2 and ATF7 was detected mainly in the crypts of the small intestine and the lower crypt region of the colonic epithelium. Under homeostatic conditions, no major phenotypic changes were detectable in the intestine of ATF mutant mice. However, on DSS exposure or whole-body irradiation, the intestinal epithelium showed a clearly impaired regenerative response. Mutant mice developed severe ulceration and inflammation associated with increased epithelial apoptosis on DSS exposure and were less able to regenerate colonic crypts on irradiation. In vitro, organoids derived from double-mutant epithelium had a growth disadvantage compared with wild-type organoids, impaired wound healing capacity in scratch assay, and increased sensitivity to tumor necrosis factor-?-induced damage. CONCLUSIONS: ATF2 and ATF7 are dispensable for epithelial homeostasis, but are required to maintain epithelial regenerative capacity and protect against cell death during intestinal epithelial damage and repair.en
dc.language.isoenen
dc.relation.urlhttps://dx.doi.org/10.1016/j.ccell.2019.12.003en
dc.titleMyosin II reactivation and cytoskeletal remodeling as a hallmark and a vulnerability in melanoma therapy resistanceen
dc.typeArticleen
dc.contributor.departmentBarts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London EC1M 6BQ, UK;en
dc.identifier.journalCancer Cellen
dc.description.noteen]
refterms.dateFOA2020-03-04T11:30:07Z


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