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","12574"],["dc.bibliographiccitation.issue","14"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","12586"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Srinivas, Upadhyayula Sai"],["dc.contributor.author","Dyczkowski, Jerzy"],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Mansour, Wael Y."],["dc.contributor.author","Borgmann, Kerstin"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2019-07-09T11:42:37Z"],["dc.date.available","2019-07-09T11:42:37Z"],["dc.date.issued","2015-05-20"],["dc.description.abstract","Malignant tumors of the rectum are treated by neoadjuvant radiochemotherapy. This involves a combination of 5-fluorouracil (5-FU) and double stranded DNA-break (DSB)-inducing radiotherapy. Here we explored how 5-FU cooperates with DSB-induction to achieve sustainable DNA damage in colorectal cancer (CRC) cells. After DSB induction by neocarzinostatin, phosphorylated histone 2AX (γ-H2AX) rapidly accumulated but then largely vanished within a few hours. In contrast, when CRC cells were pre-treated with 5-FU, gammaH2AX remained for at least 24 hours. GFP-reporter assays revealed that 5-FU decreases the efficiency of homologous recombination (HR) repair. However, 5-FU did not prevent the initial steps of HR repair, such as the accumulation of RPA and Rad51 at nuclear foci. Thus, we propose that 5-FU interferes with the continuation of HR repair, e. g. the synthesis of new DNA strands. Two key mediators of HR, Rad51 and BRCA2, were found upregulated in CRC biopsies as compared to normal mucosa. Inhibition of HR by targeting Rad51 enhanced DNA damage upon DSB-inducing treatment, outlining an alternative way of enhancing therapeutic efficacy. Taken together, our results strongly suggest that interfering with HR represents a key mechanism to enhance the efficacy when treating CRC with DNA-damaging therapy."],["dc.identifier.doi","10.18632/oncotarget.3728"],["dc.identifier.fs","612071"],["dc.identifier.pmid","25909291"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13608"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58708"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1949-2553"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.subject.mesh","Antineoplastic Agents"],["dc.subject.mesh","Cell Line, Tumor"],["dc.subject.mesh","Chemoradiotherapy"],["dc.subject.mesh","Colorectal Neoplasms"],["dc.subject.mesh","DNA Breaks, Double-Stranded"],["dc.subject.mesh","Flow Cytometry"],["dc.subject.mesh","Fluorouracil"],["dc.subject.mesh","Humans"],["dc.subject.mesh","Immunoblotting"],["dc.subject.mesh","Microscopy, Confocal"],["dc.subject.mesh","Microscopy, Fluorescence"],["dc.subject.mesh","Oligonucleotide Array Sequence Analysis"],["dc.subject.mesh","Recombinational DNA Repair"],["dc.subject.mesh","Reverse Transcriptase Polymerase Chain Reaction"],["dc.title","5-Fluorouracil sensitizes colorectal tumor cells towards double stranded DNA breaks by interfering with homologous recombination repair."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]