Najafova, Zeynab

[["dc.bibliographiccitation.firstpage","3145"],["dc.bibliographiccitation.issue","13"],["dc.bibliographiccitation.journal","Cancers"],["dc.bibliographiccitation.volume","13"],["dc.contributor.affiliation","Walter, Karolin; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, karolin.walter@uni-ulm.de"],["dc.contributor.affiliation","Rodriguez-Aznar, Eva; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, eva.rodriguez-aznar@uni-ulm.de"],["dc.contributor.affiliation","Ferreira, Monica S. Ventura; \t\t \r\n\t\t Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 52062 Aachen, Germany, monicasvferreira@gmail.com"],["dc.contributor.affiliation","Frappart, Pierre-Olivier; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, pfrappar@uni-mainz.de\t\t \r\n\t\t Institute of Toxicology, University Medical Centre of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany, pfrappar@uni-mainz.de"],["dc.contributor.affiliation","Dittrich, Tabea; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, tabea.dittrich@uni-ulm.de"],["dc.contributor.affiliation","Tiwary, Kanishka; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, kanishka.tiwary@uni-ulm.de"],["dc.contributor.affiliation","Meessen, Sabine; \t\t \r\n\t\t Department of Urology, Ulm University, 89081 Ulm, Germany, sabine.meessen@uni-ulm.de"],["dc.contributor.affiliation","Lerma, Laura; \t\t \r\n\t\t Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain, lerma.laura@gmail.com"],["dc.contributor.affiliation","Daiss, Nora; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, nora.daiss@uniklinik-ulm.de"],["dc.contributor.affiliation","Schulte, Lucas-Alexander; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, lucas-alexander.schulte@uniklinik-ulm.de"],["dc.contributor.affiliation","Najafova, Zeynab; \t\t \r\n\t\t Department of Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany, zeynab.najafova@med.uni-goettingen.de"],["dc.contributor.affiliation","Arnold, Frank; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, frank.arnold@uni-ulm.de"],["dc.contributor.affiliation","Usachov, Valentyn; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, usachovatn@yahoo.com"],["dc.contributor.affiliation","Azoitei, Ninel; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, ninel.azoitei@uniklinik-ulm.de"],["dc.contributor.affiliation","Erkan, Mert; \t\t \r\n\t\t Department of Surgery, Koç University School of Medicine, Istanbul 34450, Turkey, merkan@ku.edu.tr\t\t \r\n\t\t Research Center for Translational Medicine, Koç University, Istanbul 34450, Turkey, merkan@ku.edu.tr"],["dc.contributor.affiliation","Lechel, Andre; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, andre.lechel@uniklinik-ulm.de"],["dc.contributor.affiliation","Brümmendorf, Tim H.; \t\t \r\n\t\t Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 52062 Aachen, Germany, tbruemmendorf@ukaachen.de"],["dc.contributor.affiliation","Seufferlein, Thomas; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, thomas.seufferlein@uni-ulm.de"],["dc.contributor.affiliation","Kleger, Alexander; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, alexander.kleger@uni-ulm.de"],["dc.contributor.affiliation","Tabarés, Enrique; \t\t \r\n\t\t Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain, enrique.tabares@uam.es"],["dc.contributor.affiliation","Günes, Cagatay; \t\t \r\n\t\t Department of Urology, Ulm University, 89081 Ulm, Germany, cagatay.guenes@uniklinik-ulm.de"],["dc.contributor.affiliation","Johnsen, Steven A.; \t\t \r\n\t\t Gene Regulatory Mechanisms and Molecular Epigenetics Lab, Gastroenterology Research, Mayo Clinic, Rochester, MN 55905, USA, Johnsen.Steven@mayo.edu"],["dc.contributor.affiliation","Beier, Fabian; \t\t \r\n\t\t Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 52062 Aachen, Germany, fbeier@ukaachen.de"],["dc.contributor.affiliation","Sainz, Bruno; \t\t \r\n\t\t Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain, bsainz@iib.uam.es\t\t \r\n\t\t Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, 28049 Madrid, Spain, bsainz@iib.uam.es\t\t \r\n\t\t Chronic Diseases and Cancer, Area 3—Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28049 Madrid, Spain, bsainz@iib.uam.es"],["dc.contributor.affiliation","Hermann, Patrick C.; \t\t \r\n\t\t Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany, patrick.hermann@uni-ulm.de"],["dc.contributor.author","Walter, Karolin"],["dc.contributor.author","Rodriguez-Aznar, Eva"],["dc.contributor.author","Ferreira, Monica S. Ventura"],["dc.contributor.author","Frappart, Pierre-Olivier"],["dc.contributor.author","Dittrich, Tabea"],["dc.contributor.author","Tiwary, Kanishka"],["dc.contributor.author","Meessen, Sabine"],["dc.contributor.author","Lerma, Laura"],["dc.contributor.author","Daiss, Nora"],["dc.contributor.author","Hermann, Patrick C."],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Johnsen, Steven A."],["dc.contributor.author","Schulte, Lucas-Alexander"],["dc.contributor.author","Arnold, Frank"],["dc.contributor.author","Usachov, Valentyn"],["dc.contributor.author","Azoitei, Ninel"],["dc.contributor.author","Erkan, Mert"],["dc.contributor.author","Lechel, Andre"],["dc.contributor.author","Brümmendorf, Tim H."],["dc.contributor.author","Seufferlein, Thomas"],["dc.contributor.author","Kleger, Alexander"],["dc.contributor.author","Tabarés, Enrique"],["dc.contributor.author","Günes, Cagatay"],["dc.contributor.author","Beier, Fabian"],["dc.contributor.author","Sainz, Bruno"],["dc.date.accessioned","2021-08-12T07:45:52Z"],["dc.date.available","2021-08-12T07:45:52Z"],["dc.date.issued","2021"],["dc.date.updated","2022-02-09T13:20:51Z"],["dc.description.abstract","To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients."],["dc.description.abstract","To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients."],["dc.description.sponsorship","Deutsche Krebshilfe"],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft"],["dc.description.sponsorship","Medizinische Fakultät, Universität Ulm"],["dc.description.sponsorship","Hector Foundation"],["dc.identifier.doi","10.3390/cancers13133145"],["dc.identifier.eissn","2072-6694"],["dc.identifier.pii","cancers13133145"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/88563"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-448"],["dc.publisher","MDPI"],["dc.relation.eissn","2072-6694"],["dc.rights","https://creativecommons.org/licenses/by/4.0/"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0/"],["dc.title","Telomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","6334"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Nucleic Acids Research"],["dc.bibliographiccitation.lastpage","6349"],["dc.bibliographiccitation.volume","45"],["dc.contributor.author","Mishra, Vivek Kumar"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Kosinsky, Robyn Laura"],["dc.contributor.author","Sen, Madhobi"],["dc.contributor.author","Baumgartner, Roland"],["dc.contributor.author","Wulff, Tanja"],["dc.contributor.author","Siveke, Jens T."],["dc.contributor.author","Schildhaus, Hans-Ulrich"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Kari, Vijayalakshmi"],["dc.contributor.author","Kohlhof, Hella"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2018-11-07T10:22:37Z"],["dc.date.available","2018-11-07T10:22:37Z"],["dc.date.issued","2017"],["dc.description.abstract","Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a particularly dismal prognosis. Histone deacetylases (HDAC) are epigenetic modulators whose activity is frequently deregulated in various cancers including PDAC. In particular, class-I HDACs (HDAC 1, 2, 3 and 8) have been shown to play an important role in PDAC. In this study, we investigated the effects of the class Ispecific HDAC inhibitor (HDACi) 4SC-202 in multiple PDAC cell lines in promoting tumor cell differentiation. We show that 4SC-202 negatively affects TGF beta signaling and inhibits TGF beta-induced epithelial-tomesenchymal transition (EMT). Moreover, 4SC-202 markedly induced p21 (CDKN1A) expression and significantly attenuated cell proliferation. Mechanistically, genome-wide studies revealed that 4SC-202-induced genes were enriched for Bromodomain-containing Protein-4 (BRD4) and MYC occupancy. BRD4, a well-characterized acetyllysine reader, has been shown to play a major role in regulating transcription of selected subsets of genes. Importantly, BRD4 and MYC are essential for the expression of a subgroup of genes induced by class-I HDACi. Taken together, our study uncovers a previously unknown role of BRD4 and MYC in eliciting the HDACi-mediated induction of a subset of genes and provides molecular insight into the mechanisms of HDACi action in PDAC."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2017"],["dc.identifier.doi","10.1093/nar/gkx212"],["dc.identifier.isi","000403693000023"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14605"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42309"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","1362-4962"],["dc.relation.issn","0305-1048"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4-and MYC-dependent manner"],["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","32"],["dc.bibliographiccitation.journal","Genome Biology"],["dc.bibliographiccitation.volume","18"],["dc.contributor.author","Xie, Wanhua"],["dc.contributor.author","Nagarajan, Sankari"],["dc.contributor.author","Baumgart, Simon J."],["dc.contributor.author","Kosinsky, Robyn Laura"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Kari, Vijayalakshmi"],["dc.contributor.author","Hennion, Magali"],["dc.contributor.author","Indenbirken, Daniela"],["dc.contributor.author","Bonn, Stefan"],["dc.contributor.author","Grundhoff, Adam"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Mansouri, Ahmed"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2018-11-07T10:27:18Z"],["dc.date.available","2018-11-07T10:27:18Z"],["dc.date.issued","2017"],["dc.description.abstract","Background: Monoubiquitination of H2B (H2Bub1) is a largely enigmatic histone modification that has been linked to transcriptional elongation. Because of this association, it has been commonly assumed that H2Bub1 is an exclusively positively acting histone modification and that increased H2Bub1 occupancy correlates with increased gene expression. In contrast, depletion of the H2B ubiquitin ligases RNF20 or RNF40 alters the expression of only a subset of genes. Results: Using conditional Rnf40 knockout mouse embryo fibroblasts, we show that genes occupied by low to moderate amounts of H2Bub1 are selectively regulated in response to Rnf40 deletion, whereas genes marked by high levels of H2Bub1 are mostly unaffected by Rnf40 loss. Furthermore, we find that decreased expression of RNF40-dependent genes is highly associated with widespread narrowing of H3K4me3 peaks. H2Bub1 promotes the broadening of H3K4me3 to increase transcriptional elongation, which together lead to increased tissue- specific gene transcription. Notably, genes upregulated following Rnf40 deletion, including Foxl2, are enriched for H3K27me3, which is decreased following Rnf40 deletion due to decreased expression of the Ezh2 gene. As a consequence, increased expression of some RNF40-\"suppressed\" genes is associated with enhancer activation via FOXL2. Conclusion: Together these findings reveal the complexity and context-dependency whereby one histone modification can have divergent effects on gene transcription. Furthermore, we show that these effects are dependent upon the activity of other epigenetic regulatory proteins and histone modifications."],["dc.identifier.doi","10.1186/s13059-017-1159-5"],["dc.identifier.isi","000394828000003"],["dc.identifier.pmid","28209164"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14250"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43221"],["dc.notes.intern","Merged from goescholar"],["dc.notes.intern","In goescholar not merged with http://resolver.sub.uni-goettingen.de/purl?gs-1/14993 but duplicate"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Biomed Central Ltd"],["dc.relation.issn","1474-760X"],["dc.rights","CC BY 4.0"],["dc.rights.access","openAccess"],["dc.rights.holder","The Author(s)."],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","RNF40 regulates gene expression in an epigenetic context-dependent manner"],["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","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.firstpage","3130"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Nucleic Acids Research"],["dc.bibliographiccitation.lastpage","3145"],["dc.bibliographiccitation.volume","45"],["dc.contributor.author","Nagarajan, Sankari"],["dc.contributor.author","Bedi, Upasana"],["dc.contributor.author","Budida, Anusha"],["dc.contributor.author","Hamdan, Feda H."],["dc.contributor.author","Mishra, Vivek Kumar"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Xie, Wanhua"],["dc.contributor.author","Alawi, Malik"],["dc.contributor.author","Indenbirken, Daniela"],["dc.contributor.author","Knapp, Stefan"],["dc.contributor.author","Chiang, Cheng-Ming"],["dc.contributor.author","Grundhoff, Adam"],["dc.contributor.author","Kari, Vijayalakshmi"],["dc.contributor.author","Scheel, Christina H."],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2018-11-07T10:25:04Z"],["dc.date.available","2018-11-07T10:25:04Z"],["dc.date.issued","2017"],["dc.description.abstract","Bromodomain-containing protein 4 (BRD4) is a member of the bromo-and extraterminal (BET) domain-containing family of epigenetic readers which is under intensive investigation as a target for anti-tumor therapy. BRD4 plays a central role in promoting the expression of select subsets of genes including many driven by oncogenic transcription factors and signaling pathways. However, the role of BRD4 and the effects of BET inhibitors in non-transformed cells remain mostly unclear. We demonstrate that BRD4 is required for the maintenance of a basal epithelial phenotype by regulating the expression of epithelial-specific genes including TP63 and Grainy Head-like transcription factor-3 (GRHL3) in non-transformed basal-like mammary epithelial cells. Moreover, BRD4 occupancy correlates with enhancer activity and enhancer RNA (eRNA) transcription. Motif analyses of cell context-specific BRD4-enriched regions predicted the involvement of FOXOtranscription factors. Consistently, activation of FOXO1 function via inhibition of EGFR-AKT signaling promoted the expression of TP63 and GRHL3. Moreover, activation of Src kinase signaling and FOXO1 inhibition decreased the expression of FOXO/BRD4 target genes. Together, our findings support a function for BRD4 in promoting basal mammary cell epithelial differentiation, at least in part, by regulating FOXO factor function on enhancers to activate TP63 and GRHL3 expression."],["dc.identifier.doi","10.1093/nar/gkw1276"],["dc.identifier.isi","000398376200026"],["dc.identifier.pmid","27980063"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14764"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42778"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","1362-4962"],["dc.relation.issn","0305-1048"],["dc.rights","CC BY-NC 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc/4.0"],["dc.title","BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["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"]]

[["dc.bibliographiccitation.firstpage","459"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Cell Reports"],["dc.bibliographiccitation.lastpage","468"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Nagarajan, Sankari"],["dc.contributor.author","Hossan, Tareq"],["dc.contributor.author","Alawi, Malik"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Indenbirken, Daniela"],["dc.contributor.author","Bedi, Upasana"],["dc.contributor.author","Taipaleenmaeki, Hanna"],["dc.contributor.author","Ben-Batalla, Isabel"],["dc.contributor.author","Scheller, Marina"],["dc.contributor.author","Loges, Sonja"],["dc.contributor.author","Knapp, Stefan"],["dc.contributor.author","Hesse, Eric"],["dc.contributor.author","Chiang, Cheng-Ming"],["dc.contributor.author","Grundhoff, Adam"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2018-11-07T09:37:31Z"],["dc.date.available","2018-11-07T09:37:31Z"],["dc.date.issued","2014"],["dc.description.abstract","The estrogen receptor alpha (ER alpha) controls cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to control gene transcription. A deeper understanding of these transcriptional mechanisms may uncover therapeutic targets for ER alpha-dependent cancers. We show that BRD4 regulates ER alpha-induced gene expression by affecting elongation-associated phosphorylation of RNA polymerase II (RNAPII) and histone H2B monoubiquitination. Consistently, BRD4 activity is required for proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide studies revealed an enrichment of BRD4 on transcriptional start sites of active genes and a requirement of BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we demonstrate that BRD4 occupancy on distal EREs enriched for H3K27ac is required for recruitment and elongation of RNAPII on EREs and the production of ER alpha-dependent enhancer RNAs. These results uncover BRD4 as a central regulator of ER alpha function and potential therapeutic target."],["dc.identifier.doi","10.1016/j.celrep.2014.06.016"],["dc.identifier.isi","000341569800016"],["dc.identifier.pmid","25017071"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11372"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/32862"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Cell Press"],["dc.relation.issn","2211-1247"],["dc.rights","CC BY-NC-ND 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/3.0"],["dc.title","Bromodomain Protein BRD4 Is Required for Estrogen Receptor-Dependent Enhancer Activation and Gene Transcription"],["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","127"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nucleic Acids Research"],["dc.bibliographiccitation.lastpage","141"],["dc.bibliographiccitation.volume","45"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Tirado-Magallanes, Roberto"],["dc.contributor.author","Subramaniam, Malayannan"],["dc.contributor.author","Hossan, Tareq"],["dc.contributor.author","Schmidt, Geske"],["dc.contributor.author","Nagarajan, Sankari"],["dc.contributor.author","Baumgart, Simon J."],["dc.contributor.author","Mishra, Vivek Kumar"],["dc.contributor.author","Bedi, Upasana"],["dc.contributor.author","Hesse, Eric"],["dc.contributor.author","Knapp, Stefan"],["dc.contributor.author","Hawse, John R."],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2018-11-07T10:28:57Z"],["dc.date.available","2018-11-07T10:28:57Z"],["dc.date.issued","2017"],["dc.description.abstract","Proper temporal epigenetic regulation of gene expression is essential for cell fate determination and tissue development. The Bromodomain-containing Protein-4 (BRD4) was previously shown to control the transcription of defined subsets of genes in various cell systems. In this study we examined the role of BRD4 in promoting lineage-specific gene expression and show that BRD4 is essential for osteoblast differentiation. Genome-wide analyses demonstrate that BRD4 is recruited to the transcriptional start site of differentiation-induced genes. Unexpectedly, while promoter-proximal BRD4 occupancy correlated with gene expression, genes which displayed moderate expression and promoter-proximal BRD4 occupancy were most highly regulated and sensitive to BRD4 inhibition. Therefore, we examined distal BRD4 occupancy and uncovered a specific co-localization of BRD4 with the transcription factors C/EBPb, TEAD1, FOSL2 and JUND at putative osteoblast-specific enhancers. These findings reveal the intricacies of lineage specification and provide new insight into the context-dependent functions of BRD4."],["dc.identifier.doi","10.1093/nar/gkw826"],["dc.identifier.isi","000396575100016"],["dc.identifier.pmid","27651452"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14409"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43538"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","1362-4962"],["dc.relation.issn","0305-1048"],["dc.rights","CC BY-NC 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc/4.0"],["dc.title","BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire"],["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","4"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Clinical Epigenetics"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Kari, Vijayalakshmi"],["dc.contributor.author","Raul, Sanjay K"],["dc.contributor.author","Henck, Jana M"],["dc.contributor.author","Kitz, Julia"],["dc.contributor.author","Kramer, Frank"],["dc.contributor.author","Kosinsky, Robyn L"],["dc.contributor.author","Übelmesser, Nadine"],["dc.contributor.author","Mansour, Wael Y"],["dc.contributor.author","Eggert, Jessica"],["dc.contributor.author","Spitzner, Melanie"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Bastians, Holger"],["dc.contributor.author","Grade, Marian"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Johnsen, Steven A"],["dc.date.accessioned","2019-07-09T11:49:49Z"],["dc.date.available","2019-07-09T11:49:49Z"],["dc.date.issued","2019"],["dc.description.abstract","Abstract Background Disruptor of telomeric silencing 1-like (DOT1L) is a non-SET domain containing methyltransferase known to catalyze mono-, di-, and tri-methylation of histone 3 on lysine 79 (H3K79me). DOT1L-mediated H3K79me has been implicated in chromatin-associated functions including gene transcription, heterochromatin formation, and DNA repair. Recent studies have uncovered a role for DOT1L in the initiation and progression of leukemia and other solid tumors. The development and availability of small molecule inhibitors of DOT1L may provide new and unique therapeutic options for certain types or subgroups of cancer. Methods In this study, we examined the role of DOT1L in DNA double-strand break (DSB) response and repair by depleting DOT1L using siRNA or inhibiting its methyltransferase activity using small molecule inhibitors in colorectal cancer cells. Cells were treated with different agents to induce DNA damage in DOT1L-depleted or -inhibited cells and analyzed for DNA repair efficiency and survival. Further, rectal cancer patient samples were analyzed for H3K79me3 levels in order to determine whether it may serve as a potential marker for personalized therapy. Results Our results indicate that DOT1L is required for a proper DNA damage response following DNA double-strand breaks by regulating the phosphorylation of the variant histone H2AX (γH2AX) and repair via homologous recombination (HR). Importantly, we show that small molecule inhibitors of DOT1L combined with chemotherapeutic agents that are used to treat colorectal cancers show additive effects. Furthermore, examination of H3K79me3 levels in rectal cancer patients demonstrates that lower levels correlate with a poorer prognosis. Conclusions In this study, we conclude that DOT1L plays an important role in an early DNA damage response and repair of DNA double-strand breaks via the HR pathway. Moreover, DOT1L inhibition leads to increased sensitivity to chemotherapeutic agents and PARP inhibition, which further highlights its potential clinical utility. Our results further suggest that H3K79me3 can be useful as a predictive and or prognostic marker for rectal cancer patients."],["dc.identifier.doi","10.1186/s13148-018-0601-1"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15787"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59638"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","BioMed Central"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","The histone methyltransferase DOT1L is required for proper DNA damage response, DNA repair, and modulates chemotherapy responsiveness"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]