Dobbelstein, Matthias

[["dc.bibliographiccitation.firstpage","11778"],["dc.bibliographiccitation.issue","23"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","11791"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Keitel, Ulrike"],["dc.contributor.author","Scheel, Andreas"],["dc.contributor.author","Thomale, Jürgen"],["dc.contributor.author","Halpape, Rovena"],["dc.contributor.author","Kaulfuß, Silke"],["dc.contributor.author","Scheel, Christina"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2022-03-01T11:44:20Z"],["dc.date.available","2022-03-01T11:44:20Z"],["dc.date.issued","2014"],["dc.description.abstract","The transition from an epithelial to a mesenchymal phenotype (EMT) confers increased invasiveness and clonogenic potential to tumor cells. We used a breast epithelium-derived cell culture model to evaluate the impact of EMT on the cellular sensitivity towards chemotherapeutics and apoptotic stimuli. Cells that had passed through an EMT acquired resistance towards chemotherapeutics and death ligands. Mechanistically, we found that the levels of the apoptosis inhibitor Bcl-xL were strongly enhanced in mesenchymal versus epithelial cells, whereas the pro-apoptotic proteins Bim and Puma were diminished. Clinical samples from breast cancer showed enhanced Bcl-xL staining in cells that had dispersed into the desmoplastic stroma, as compared to cells that were part of large tumor cell aggregates, suggesting increased Bcl-xL expression when cells invade the stroma. Bcl-xL was necessary for apoptotic resistance in mesenchymal cells, and its expression was sufficient to confer such resistance to epithelial cells. To antagonize Bcl-xL, BH3-mimetics were used. They successfully interfered with the proliferation and survival of mesenchymal cells, and also inhibited the growth of xenograft tumors raised from the mesenchymal subpopulation. We conclude that enhanced Bcl-xL levels confer resistance to cells upon EMT, and that Bcl-xL represents a promising target for therapy directed against invasive cancer cells."],["dc.format.extent","14"],["dc.identifier.doi","10.18632/oncotarget.2634"],["dc.identifier.fs","610572"],["dc.identifier.pii","2634"],["dc.identifier.pmid","25473892"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11133"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102995"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1949-2553"],["dc.relation.issn","1949-2553"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.subject.ddc","610"],["dc.title","Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["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"]]