Dobbelstein, Matthias

[["dc.bibliographiccitation.firstpage","13072"],["dc.bibliographiccitation.issue","15"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","13087"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Saini, Priyanka"],["dc.contributor.author","Li, Yizhu"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2021-11-22T14:31:35Z"],["dc.date.available","2021-11-22T14:31:35Z"],["dc.date.issued","2015"],["dc.description.abstract","The therapeutic efficacy of nucleoside analogues, e.g. gemcitabine, against cancer cells can be augmented by inhibitors of checkpoint kinases, including Wee1, ATR, and Chk1. We have compared the chemosensitizing effect of these inhibitors in cells derived from pancreatic cancer, a tumor entity where gemcitabine is part of the first-line therapeutic regimens, and in osteosarcoma-derived cells. As expected, all three inhibitors rendered cancer cells more sensitive to gemcitabine, but Wee1 inhibition proved to be particularly efficient in this context. Investigating the reasons for this potent sensitizing effect, we found that Wee1 inhibition or knockdown not only blocked Wee1 activity, but also reduced the activation of ATR/Chk1 in gemcitabine-treated cells. Combination of several inhibitors revealed that Wee1 inhibition requires Cyclin-dependent kinases 1 and 2 (Cdk1/2) and Polo-like kinase 1 (Plk1) to reduce ATR/Chk1 activity. Through activation of Cdks and Plk1, Wee1 inhibition reduces Claspin and CtIP levels, explaining the impairment in ATR/Chk1 activity. Taken together, these results confer a consistent signaling pathway reaching from Wee1 inhibition to impaired Chk1 activity, mechanistically dissecting how Wee1 inhibitors not only dysregulate cell cycle progression, but also enhance replicative stress and chemosensitivity towards nucleoside analogues."],["dc.identifier.doi","10.18632/oncotarget.3865"],["dc.identifier.fs","612801"],["dc.identifier.isi","000359009400018"],["dc.identifier.pmid","25965828"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13619"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/93390"],["dc.language","eng"],["dc.language.iso","en"],["dc.notes.intern","Migrated 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.access","openAccess"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.subject","Wee1, ATR signaling pathway, replicative stress, checkpoint kinases, gemcitabine"],["dc.subject.mesh","Antimetabolites, Antineoplastic"],["dc.subject.mesh","Antineoplastic Combined Chemotherapy Protocols"],["dc.subject.mesh","Ataxia Telangiectasia Mutated Proteins"],["dc.subject.mesh","Cell Cycle Proteins"],["dc.subject.mesh","Cell Line, Tumor"],["dc.subject.mesh","Deoxycytidine"],["dc.subject.mesh","Drug Synergism"],["dc.subject.mesh","Humans"],["dc.subject.mesh","Nuclear Proteins"],["dc.subject.mesh","Pancreatic Neoplasms"],["dc.subject.mesh","Protein Kinase Inhibitors"],["dc.subject.mesh","Protein Kinases"],["dc.subject.mesh","Protein-Tyrosine Kinases"],["dc.subject.mesh","Signal Transduction"],["dc.title","Wee1 is required to sustain ATR/Chk1 signaling upon replicative stress."],["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.firstpage","32339"],["dc.bibliographiccitation.issue","32"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","32352"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Li, Yizhu"],["dc.contributor.author","Saini, Priyanka"],["dc.contributor.author","Sriraman, Anusha"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T09:50:04Z"],["dc.date.available","2018-11-07T09:50:04Z"],["dc.date.issued","2015"],["dc.description.abstract","Pharmacological inhibition of the cell cycle regulatory kinase Wee1 represents a promising strategy to eliminate cancer cells. Wee1 inhibitors cooperate with chemotherapeutics, e.g. nucleoside analogues, pushing malignant cells from S phase towards premature mitosis and death. However, considerable toxicities are observed in preclinical and clinical trials. A high proportion of tumor cells can be distinguished from all other cells of a patient's body by inactivating mutations in the tumor suppressor p53. Here we set out to develop an approach for the selective protection of p53-proficient cells against the cytotoxic effects of Wee1 inhibitors. We pretreated such cells with Nutlin-3a, a prototype inhibitor of the p53-antagonist Mdm2. The resulting transient cell cycle arrest effectively increased the survival of cells that were subsequently treated with combinations of the Wee1 inhibitor MK1775 and/or the nucleoside analogue gemcitabine. In this constellation, Nutlin-3a reduced caspase activation and diminished the phosphorylation of Histone 2AX, an indicator of the DNA damage response. Both effects were strictly dependent on the presence of p53. Moreover, Nutlin pre-treatment reduced the fraction of cells that were undergoing premature mitosis in response to Wee1 inhibition. We conclude that the pre-activation of p53 through Mdm2 antagonists serves as a viable option to selectively protect p53-proficient cells against the cytotoxic effects of Wee1 inhibitors, especially when combined with a nucleoside analogue. Thus, Mdm2 antagonists might prove useful to avoid unwanted side effects of Wee1 inhibitors. On the other hand, when a tumor contains wild type p53, care should be taken not to induce its activity before applying Wee1 inhibitors."],["dc.identifier.doi","10.18632/oncotarget.5891"],["dc.identifier.isi","000363186600021"],["dc.identifier.pmid","26431163"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12729"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/35637"],["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","Mdm2 inhibition confers protection of p53-proficient cells from the cytotoxic effects of Wee1 inhibitors"],["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.firstpage","16856"],["dc.bibliographiccitation.issue","42"],["dc.bibliographiccitation.journal","Proceedings of the National Academy of Sciences of the United States of America"],["dc.bibliographiccitation.lastpage","16861"],["dc.bibliographiccitation.volume","110"],["dc.contributor.author","Koepper, Frederik"],["dc.contributor.author","Bierwirth, Cathrin"],["dc.contributor.author","Schoen, Margarete"],["dc.contributor.author","Kunze, Meike"],["dc.contributor.author","Elvers, Ingegerd"],["dc.contributor.author","Kranz, Dominique"],["dc.contributor.author","Saini, Priyanka"],["dc.contributor.author","Menon, Manoj B."],["dc.contributor.author","Walter, David"],["dc.contributor.author","Sorensen, Claus Storgaard"],["dc.contributor.author","Gaestel, Matthias"],["dc.contributor.author","Helleday, Thomas"],["dc.contributor.author","Schoen, Michael Peter"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T09:18:38Z"],["dc.date.available","2018-11-07T09:18:38Z"],["dc.date.issued","2013"],["dc.description.abstract","DNA damage can obstruct replication forks, resulting in replicative stress. By siRNA screening, we identified kinases involved in the accumulation of phosphohistone 2AX (gamma H2AX) upon UV irradiation-induced replication stress. Surprisingly, the strongest reduction of phosphohistone 2AX followed knockdown of the MAP kinase-activated protein kinase 2 (MK2), a kinase currently implicated in p38 stress signaling and G2 arrest. Depletion or inhibition of MK2 also protected cells from DNA damage-induced cell death, and mice deficient for MK2 displayed decreased apoptosis in the skin upon UV irradiation. Moreover, MK2 activity was required for damage response, accumulation of ssDNA, and decreased survival when cells were treated with the nucleoside analogue gemcitabine or when the checkpoint kinase Chk1 was antagonized. By using DNA fiber assays, we found that MK2 inhibition or knockdown rescued DNA replication impaired by gemcitabine or by Chk1 inhibition. This rescue strictly depended on transiesion DNA polymerases. In conclusion, instead of being an unavoidable consequence of DNA damage, alterations of replication speed and origin firing depend on MK2-mediated signaling."],["dc.identifier.doi","10.1073/pnas.1304355110"],["dc.identifier.isi","000325634200042"],["dc.identifier.pmid","24082115"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/28446"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Natl Acad Sciences"],["dc.relation.issn","0027-8424"],["dc.title","Damage-induced DNA replication stalling relies on MAPK-activated protein kinase 2 activity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]