Dobbelstein, Matthias

[["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","Cell Death & Disease"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Choo, Josephine Ann Mun Yee"],["dc.contributor.author","Schlösser, Denise"],["dc.contributor.author","Manzini, Valentina"],["dc.contributor.author","Magerhans, Anna"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2021-04-14T08:24:30Z"],["dc.date.available","2021-04-14T08:24:30Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1038/s41419-020-2727-2"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17479"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81303"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.notes.intern","Merged from goescholar"],["dc.relation.eissn","2041-4889"],["dc.relation.haserratum","/handle/2/86727"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","The integrated stress response induces R-loops and hinders replication fork progression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","6163"],["dc.bibliographiccitation.issue","24"],["dc.bibliographiccitation.journal","Cancers"],["dc.bibliographiccitation.volume","13"],["dc.contributor.affiliation","Ewers, Katharina M.; 1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany; katharina.ewers@med.uni-goettingen.de (K.M.E.); tabea.quilitz@stud.uni-goettingen.de (T.Q.); anna.magerhans@med.uni-goettingen.de (A.M.)"],["dc.contributor.affiliation","Patil, Shilpa; 2Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075 Göttingen, Germany; shilpapatil528@gmail.com (S.P.); wkopp@med.uni-goettingen.de (W.K.); elisabeth.hessmann@med.uni-goettingen.de (E.H.)"],["dc.contributor.affiliation","Kopp, Waltraut; 2Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075 Göttingen, Germany; shilpapatil528@gmail.com (S.P.); wkopp@med.uni-goettingen.de (W.K.); elisabeth.hessmann@med.uni-goettingen.de (E.H.)"],["dc.contributor.affiliation","Thomale, Jürgen; 4Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, 45141 Essen, Germany; juergen.thomale@uni-due.de"],["dc.contributor.affiliation","Quilitz, Tabea; 1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany; katharina.ewers@med.uni-goettingen.de (K.M.E.); tabea.quilitz@stud.uni-goettingen.de (T.Q.); anna.magerhans@med.uni-goettingen.de (A.M.)"],["dc.contributor.affiliation","Magerhans, Anna; 1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany; katharina.ewers@med.uni-goettingen.de (K.M.E.); tabea.quilitz@stud.uni-goettingen.de (T.Q.); anna.magerhans@med.uni-goettingen.de (A.M.)"],["dc.contributor.affiliation","Wang, Xin; 5Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; xin.wang@uni-goettingen.de"],["dc.contributor.affiliation","Hessmann, Elisabeth; 2Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075 Göttingen, Germany; shilpapatil528@gmail.com (S.P.); wkopp@med.uni-goettingen.de (W.K.); elisabeth.hessmann@med.uni-goettingen.de (E.H.)"],["dc.contributor.affiliation","Dobbelstein, Matthias; 1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany; katharina.ewers@med.uni-goettingen.de (K.M.E.); tabea.quilitz@stud.uni-goettingen.de (T.Q.); anna.magerhans@med.uni-goettingen.de (A.M.)"],["dc.contributor.author","Ewers, Katharina M."],["dc.contributor.author","Patil, Shilpa"],["dc.contributor.author","Kopp, Waltraut"],["dc.contributor.author","Thomale, Jürgen"],["dc.contributor.author","Quilitz, Tabea"],["dc.contributor.author","Magerhans, Anna"],["dc.contributor.author","Wang, Xin"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.editor","Wong, David"],["dc.date.accessioned","2022-02-01T10:31:44Z"],["dc.date.available","2022-02-01T10:31:44Z"],["dc.date.issued","2021"],["dc.date.updated","2022-02-09T13:20:08Z"],["dc.description.abstract","To improve the treatment of pancreatic ductal adenocarcinoma (PDAC), a promising strategy consists of personalized chemotherapy based on gene expression profiles. Investigating a panel of PDAC-derived human cell lines, we found that their sensitivities towards cisplatin fall in two distinct classes. The platinum-sensitive class is characterized by the expression of GATA6, miRNA-200a, and miRNA-200b, which might be developable as predictive biomarkers. In the case of resistant PDAC cells, we identified a synergism of cisplatin with HSP90 inhibitors. Mechanistic explanations of this synergy include the degradation of Fanconi anemia pathway factors upon HSP90 inhibition. Treatment with the drug combination resulted in increased DNA damage and chromosome fragmentation, as we have reported previously for ovarian cancer cells. On top of this, HSP90 inhibition also enhanced the accumulation of DNA-bound platinum. We next investigated an orthotopic syngeneic animal model consisting of tumors arising from KPC cells (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre, C57/BL6 genetic background). Here again, when treating established tumors, the combination of cisplatin with the HSP90 inhibitor onalespib was highly effective and almost completely prevented further tumor growth. We propose that the combination of platinum drugs and HSP90 inhibitors might be worth testing in the clinics for the treatment of cisplatin-resistant PDACs."],["dc.description.abstract","To improve the treatment of pancreatic ductal adenocarcinoma (PDAC), a promising strategy consists of personalized chemotherapy based on gene expression profiles. Investigating a panel of PDAC-derived human cell lines, we found that their sensitivities towards cisplatin fall in two distinct classes. The platinum-sensitive class is characterized by the expression of GATA6, miRNA-200a, and miRNA-200b, which might be developable as predictive biomarkers. In the case of resistant PDAC cells, we identified a synergism of cisplatin with HSP90 inhibitors. Mechanistic explanations of this synergy include the degradation of Fanconi anemia pathway factors upon HSP90 inhibition. Treatment with the drug combination resulted in increased DNA damage and chromosome fragmentation, as we have reported previously for ovarian cancer cells. On top of this, HSP90 inhibition also enhanced the accumulation of DNA-bound platinum. We next investigated an orthotopic syngeneic animal model consisting of tumors arising from KPC cells (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre, C57/BL6 genetic background). Here again, when treating established tumors, the combination of cisplatin with the HSP90 inhibitor onalespib was highly effective and almost completely prevented further tumor growth. We propose that the combination of platinum drugs and HSP90 inhibitors might be worth testing in the clinics for the treatment of cisplatin-resistant PDACs."],["dc.identifier.doi","10.3390/cancers13246163"],["dc.identifier.eissn","2072-6694"],["dc.identifier.pii","cancers13246163"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/98936"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-517"],["dc.publisher","MDPI"],["dc.relation.eissn","2072-6694"],["dc.rights","Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)."],["dc.title","HSP90 Inhibition Synergizes with Cisplatin to Eliminate Basal-like Pancreatic Ductal Adenocarcinoma Cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","22"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Biomolecules"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Henningsen, Kester Mo"],["dc.contributor.author","Manzini, Valentina"],["dc.contributor.author","Magerhans, Anna"],["dc.contributor.author","Gerber, Sabrina"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.editor","Uversky, Vladimir N."],["dc.date.accessioned","2022-02-01T10:31:43Z"],["dc.date.available","2022-02-01T10:31:43Z"],["dc.date.issued","2021"],["dc.date.updated","2022-02-09T13:20:10Z"],["dc.description.abstract","MDM2 is the principal antagonist of the tumor suppressor p53. p53 binds to its cognate DNA element within promoters and activates the transcription of adjacent genes. These target genes include MDM2. Upon induction by p53, the MDM2 protein binds and ubiquitinates p53, triggering its proteasomal degradation and providing negative feedback. This raises the question whether MDM2 can also remove p53 from its target promoters, and whether this also involves ubiquitination. In the present paper, we employ the MDM2-targeted small molecule Nutlin-3a (Nutlin) to disrupt the interaction of MDM2 and p53 in three different cancer cell lines: SJSA-1 (osteosarcoma), 93T449 (liposarcoma; both carrying amplified MDM2), and MCF7 (breast adenocarcinoma). Remarkably, removing Nutlin from the culture medium for less than five minutes not only triggered p53 ubiquitination, but also dissociated most p53 from its chromatin binding sites, as revealed by chromatin immunoprecipitation. This also resulted in reduced p53-responsive transcription, and it occurred much earlier than the degradation of p53 by the proteasome, arguing that MDM2 removes p53 from promoters prior to and thus independent of degradation. Accordingly, the short-term pharmacological inhibition of the proteasome did not alter the removal of p53 from promoters by Nutlin washout. However, when the proteasome inhibitor was applied for several hours, depleting non-conjugated ubiquitin prior to eliminating Nutlin, this compromised the removal of DNA-bound p53, as did an E1 ubiquitin ligase inhibitor. This suggests that the ubiquitination of p53 by MDM2 is necessary for its clearance from promoters. Depleting the MDM2 cofactor MDM4 in SJSA cells did not alter the velocity by that p53 was removed from promoters upon Nutlin washout. We conclude that MDM2 antagonizes p53 not only by covering its transactivation domain and by destabilization, but also by the rapid, ubiquitin-dependent termination of p53–chromatin interactions."],["dc.description.abstract","MDM2 is the principal antagonist of the tumor suppressor p53. p53 binds to its cognate DNA element within promoters and activates the transcription of adjacent genes. These target genes include MDM2. Upon induction by p53, the MDM2 protein binds and ubiquitinates p53, triggering its proteasomal degradation and providing negative feedback. This raises the question whether MDM2 can also remove p53 from its target promoters, and whether this also involves ubiquitination. In the present paper, we employ the MDM2-targeted small molecule Nutlin-3a (Nutlin) to disrupt the interaction of MDM2 and p53 in three different cancer cell lines: SJSA-1 (osteosarcoma), 93T449 (liposarcoma; both carrying amplified MDM2), and MCF7 (breast adenocarcinoma). Remarkably, removing Nutlin from the culture medium for less than five minutes not only triggered p53 ubiquitination, but also dissociated most p53 from its chromatin binding sites, as revealed by chromatin immunoprecipitation. This also resulted in reduced p53-responsive transcription, and it occurred much earlier than the degradation of p53 by the proteasome, arguing that MDM2 removes p53 from promoters prior to and thus independent of degradation. Accordingly, the short-term pharmacological inhibition of the proteasome did not alter the removal of p53 from promoters by Nutlin washout. However, when the proteasome inhibitor was applied for several hours, depleting non-conjugated ubiquitin prior to eliminating Nutlin, this compromised the removal of DNA-bound p53, as did an E1 ubiquitin ligase inhibitor. This suggests that the ubiquitination of p53 by MDM2 is necessary for its clearance from promoters. Depleting the MDM2 cofactor MDM4 in SJSA cells did not alter the velocity by that p53 was removed from promoters upon Nutlin washout. We conclude that MDM2 antagonizes p53 not only by covering its transactivation domain and by destabilization, but also by the rapid, ubiquitin-dependent termination of p53–chromatin interactions."],["dc.identifier.doi","10.3390/biom12010022"],["dc.identifier.eissn","2218-273X"],["dc.identifier.pii","biom12010022"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/98932"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-517"],["dc.publisher","MDPI"],["dc.relation.eissn","2218-273X"],["dc.rights","Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)."],["dc.title","MDM2-Driven Ubiquitination Rapidly Removes p53 from Its Cognate Promoters"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]