Najafova, Zeynab

[["dc.bibliographiccitation.firstpage","31623"],["dc.bibliographiccitation.issue","22"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","31638"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Sriraman, Anusha"],["dc.contributor.author","Radovanovic, Marija"],["dc.contributor.author","Wienken, Magdalena"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Li, Yizhu"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T10:14:02Z"],["dc.date.available","2018-11-07T10:14:02Z"],["dc.date.issued","2016"],["dc.description.abstract","Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e.g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists."],["dc.identifier.doi","10.18632/oncotarget.9302"],["dc.identifier.isi","000377748500002"],["dc.identifier.pmid","27183917"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14134"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40550"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Impact Journals Llc"],["dc.relation.issn","1949-2553"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.title","Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","918"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Cell Death & Disease"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Sriraman, Anusha"],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Johnsen, Steven A."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2019-07-09T11:45:55Z"],["dc.date.available","2019-07-09T11:45:55Z"],["dc.date.issued","2018"],["dc.description.abstract","The genes encoding MDM2 and CDK4 are frequently co-amplified in sarcomas, and inhibitors to both targets are approved or clinically tested for therapy. However, we show that inhibitors of MDM2 and CDK4 antagonize each other in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon MDM2 inhibition. Moreover, the p53 response was also attenuated when co-depleting MDM2 and CDK4 with siRNA, compared to MDM2 single knockdown. The complexes of p53 and MDM2, as well as CDK4 and Cyclin D1, physically associated with each other, suggesting direct regulation of p53 by CDK4. Interestingly, CDK4 inhibition did not reduce p53 binding or histone acetylation at promoters, but rather attenuated the subsequent recruitment of RNA Polymerase II. Taken together, our results suggest that caution must be used when considering combined CDK4 and MDM2 inhibition for patient treatment. Moreover, they uncover a hitherto unknown role for CDK4 and Cyclin D1 in sustaining p53 activity."],["dc.identifier.doi","10.1038/s41419-018-0968-0"],["dc.identifier.pmid","30206211"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15347"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59339"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","CDK4 inhibition diminishes p53 activation by MDM2 antagonists"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]