Hahn, Heidi Eva

[["dc.bibliographiccitation.firstpage","8722"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","8735"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Graab, Ulrike"],["dc.contributor.author","Hahn, Heidi"],["dc.contributor.author","Fulda, Simone"],["dc.date.accessioned","2019-07-09T11:42:39Z"],["dc.date.available","2019-07-09T11:42:39Z"],["dc.date.issued","2015-04-20"],["dc.description.abstract","We previously reported that aberrant HH pathway activation confers a poor prognosis in rhabdomyosarcoma (RMS). Searching for new treatment strategies we therefore targeted HH signaling. Here, we identify a novel synthetic lethality of concomitant inhibition of HH and PI3K/AKT/mTOR pathways in RMS by GLI1/2 inhibitor GANT61 and PI3K/mTOR inhibitor PI103. Synergistic drug interaction is confirmed by calculation of combination index (CI < 0.2). Similarly, genetic silencing of GLI1/2 significantly increases PI103-induced apoptosis. GANT61 and PI103 also synergize to induce apoptosis in cultured primary RMS cells emphasizing the clinical relevance of this combination. Importantly, GANT61/PI103 cotreatment suppresses clonogenic survival, three-dimensional sphere formation and tumor growth in an in vivo model of RMS. Mechanistic studies reveal that GANT61 and PI103 cooperate to trigger caspase-dependent apoptosis via the mitochondrial pathway, as demonstrated by several lines of evidence. First, GANT61/PI103 cotreatment increases mRNA and protein expression of NOXA and BMF, which is required for apoptosis, since knockdown of NOXA or BMF significantly reduces GANT61/PI103-induced apoptosis. Second, GANT61/PI103 cotreatment triggers BAK/BAX activation, which contributes to GANT61/PI103-mediated apoptosis, since knockdown of BAK provides protection. Third, ectopic expression of BCL-2 or non-degradable phospho-mutant MCL-1 significantly rescue GANT61/PI103-triggered apoptosis. Fourth, GANT61/PI103 cotreatment initiate activation of the caspase cascade via apoptosome-mediated cleavage of the initiator caspase-9, as indicated by changes in the cleavage pattern of caspases (e.g. accumulation of the caspase-9 p35 cleavage fragment) upon addition of the caspase inhibitor zVAD.fmk. Thus, combined GLI1/2 and PI3K/mTOR inhibition represents a promising novel approach for synergistic apoptosis induction and tumor growth reduction with implications for new treatment strategies in RMS."],["dc.identifier.doi","10.18632/oncotarget.2726"],["dc.identifier.fs","613066"],["dc.identifier.pmid","25749378"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13615"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58714"],["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","Amino Acid Chloromethyl Ketones"],["dc.subject.mesh","Animals"],["dc.subject.mesh","Apoptosis"],["dc.subject.mesh","Apoptosis Regulatory Proteins"],["dc.subject.mesh","Caspases"],["dc.subject.mesh","Cell Line, Tumor"],["dc.subject.mesh","Chick Embryo"],["dc.subject.mesh","Drug Screening Assays, Antitumor"],["dc.subject.mesh","Drug Synergism"],["dc.subject.mesh","Furans"],["dc.subject.mesh","Gene Expression Regulation, Neoplastic"],["dc.subject.mesh","Hedgehog Proteins"],["dc.subject.mesh","Humans"],["dc.subject.mesh","Kruppel-Like Transcription Factors"],["dc.subject.mesh","Molecular Targeted Therapy"],["dc.subject.mesh","Neoplasm Proteins"],["dc.subject.mesh","Nuclear Proteins"],["dc.subject.mesh","Phosphatidylinositol 3-Kinases"],["dc.subject.mesh","Protein Kinase Inhibitors"],["dc.subject.mesh","Proto-Oncogene Proteins c-akt"],["dc.subject.mesh","Pyridines"],["dc.subject.mesh","Pyrimidines"],["dc.subject.mesh","Rhabdomyosarcoma, Alveolar"],["dc.subject.mesh","Rhabdomyosarcoma, Embryonal"],["dc.subject.mesh","Signal Transduction"],["dc.subject.mesh","TOR Serine-Threonine Kinases"],["dc.subject.mesh","Transcription Factors"],["dc.title","Identification of a novel synthetic lethality of combined inhibition of hedgehog and PI3K signaling in rhabdomyosarcoma."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e93555"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Koenig, Simone"],["dc.contributor.author","Nitzki, Frauke"],["dc.contributor.author","Uhmann, Anja"],["dc.contributor.author","Dittmann, Kai"],["dc.contributor.author","Theiss-Suennemann, Jennifer"],["dc.contributor.author","Herrmann, Markus"],["dc.contributor.author","Reichardt, Holger Michael"],["dc.contributor.author","Schwendener, Reto"],["dc.contributor.author","Pukrop, Tobias"],["dc.contributor.author","Schulz-Schaeffer, Walter J."],["dc.contributor.author","Hahn, Heidi"],["dc.date.accessioned","2018-11-07T09:41:53Z"],["dc.date.available","2018-11-07T09:41:53Z"],["dc.date.issued","2014"],["dc.description.abstract","Basal cell carcinoma (BCC) belongs to the group of non-melanoma skin tumors and is the most common tumor in the western world. BCC arises due to mutations in the tumor suppressor gene Patched1 (Ptch). Analysis of the conditional Ptch knockout mouse model for BCC reveals that macrophages and dendritic cells (DC) of the skin play an important role in BCC growth restraining processes. This is based on the observation that a clodronate-liposome mediated depletion of these cells in the tumor-bearing skin results in significant BCC enlargement. The depletion of these cells does not modulate Ki67 or K10 expression, but is accompanied by a decrease in collagen-producing cells in the tumor stroma. Together, the data suggest that cutaneous macrophages and DC in the tumor microenvironment exert an antitumor effect on BCC."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft [FOR942 HA 2197/5-2]"],["dc.identifier.doi","10.1371/journal.pone.0093555"],["dc.identifier.isi","000334101100104"],["dc.identifier.pmid","24691432"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10067"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/33833"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Depletion of Cutaneous Macrophages and Dendritic Cells Promotes Growth of Basal Cell Carcinoma in Mice"],["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","341"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Genetics in Medicine"],["dc.bibliographiccitation.lastpage","351"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Schröder, Simone"],["dc.contributor.author","Li, Yun"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Bader, Ingrid"],["dc.contributor.author","Bevot, Andrea"],["dc.contributor.author","Biskup, Saskia"],["dc.contributor.author","Dreha-Kulaczewski, Steffi"],["dc.contributor.author","Christoph Korenke, G."],["dc.contributor.author","Kottke, Raimund"],["dc.contributor.author","Mayr, Johannes A."],["dc.contributor.author","Preisel, Martin"],["dc.contributor.author","Toelle, Sandra P."],["dc.contributor.author","Wente-Schulz, Sarah"],["dc.contributor.author","Wortmann, Saskia B."],["dc.contributor.author","Hahn, Heidi"],["dc.contributor.author","Boltshauser, Eugen"],["dc.contributor.author","Uhmann, Anja"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Brockmann, Knut"],["dc.date.accessioned","2021-04-14T08:31:50Z"],["dc.date.available","2021-04-14T08:31:50Z"],["dc.date.issued","2020"],["dc.description.abstract","Purpose\r\n\r\nThis study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable.\r\nMethods\r\n\r\nWe compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts.\r\nResults\r\n\r\nIn 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient–derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign.\r\nConclusion\r\n\r\nTaken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome."],["dc.identifier.doi","10.1038/s41436-020-00979-w"],["dc.identifier.pmid","33024317"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83726"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/80"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1530-0366"],["dc.relation.issn","1098-3600"],["dc.relation.workinggroup","RG Wollnik"],["dc.rights","CC BY 4.0"],["dc.title","Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3259"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","3273"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Draeger, Julia"],["dc.contributor.author","Simon-Keller, Katja"],["dc.contributor.author","Pukrop, Tobias"],["dc.contributor.author","Klemm, Florian"],["dc.contributor.author","Wilting, Joerg"],["dc.contributor.author","Sticht, Carsten"],["dc.contributor.author","Dittmann, Kai"],["dc.contributor.author","Schulz, Matthias"],["dc.contributor.author","Leuschner, Ivo"],["dc.contributor.author","Marx, Alexander"],["dc.contributor.author","Hahn, Heidi"],["dc.date.accessioned","2018-11-07T10:28:26Z"],["dc.date.available","2018-11-07T10:28:26Z"],["dc.date.issued","2017"],["dc.description.abstract","Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and show characteristics of skeletal muscle differentiation. The two major RMS subtypes in children are alveolar (ARMS) and embryonal RMS (ERMS). We demonstrate that approximately 50% of ARMS and ERMS overexpress the LEF1/TCF transcription factor LEF1 when compared to normal skeletal muscle and that LEF1 can restrain aggressiveness especially of ARMS cells. LEF1 knockdown experiments in cell lines reveal that depending on the cellular context, LEF1 can induce pro-apoptotic signals. LEF1 can also suppress proliferation, migration and invasiveness of RMS cells both in vitro and in vivo. Furthermore, LEF1 can induce myodifferentiation of the tumor cells. This may involve regulation of other LEF1/TCF factors i.e. TCF1, whereas beta-catenin activity plays a subordinate role. Together these data suggest that LEF1 rather has tumor suppressive functions and attenuates aggressiveness in a subset of RMS."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2016"],["dc.identifier.doi","10.18632/oncotarget.13887"],["dc.identifier.isi","000391506300114"],["dc.identifier.pmid","27965462"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14022"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43418"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["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","LEF1 reduces tumor progression and induces myodifferentiation in a subset of rhabdomyosarcoma"],["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","312"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Stem Cell Reports"],["dc.bibliographiccitation.lastpage","323"],["dc.bibliographiccitation.volume","3"],["dc.contributor.author","Ferent, Julien"],["dc.contributor.author","Cochard, Loic"],["dc.contributor.author","Faure, Helene"],["dc.contributor.author","Taddei, Maurizio"],["dc.contributor.author","Hahn, Heidi"],["dc.contributor.author","Ruat, Martial"],["dc.contributor.author","Traiffort, Elisabeth"],["dc.date.accessioned","2018-11-07T09:36:38Z"],["dc.date.available","2018-11-07T09:36:38Z"],["dc.date.issued","2014"],["dc.description.abstract","In the adult brain, self-renewal is essential for the persistence of neural stem cells (NSCs) throughout life, but its regulation is still poorly understood. One NSC can give birth to two NSCs or one NSC and one transient progenitor. A correct balance is necessary for the maintenance of germinal areas, and understanding the molecular mechanisms underlying NSC division mode is clearly important. Here, we report a function of the Sonic Hedgehog (SHH) receptor Patched in the direct control of long-term NSC self-renewal in the subependymal zone. We show that genetic conditional activation of SHH signaling in adult NSCs leads to their expansion and the depletion of their direct progeny. These phenotypes are associated in vitro with an increase in NSC symmetric division in a process involving NOTCH signaling. Together, our results demonstrate a tight control of adult neurogenesis and NSC renewal driven by Patched."],["dc.identifier.doi","10.1016/j.stemcr.2014.05.016"],["dc.identifier.isi","000340882400010"],["dc.identifier.pmid","25254344"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11381"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/32663"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Cell Press"],["dc.relation.issn","2213-6711"],["dc.rights","CC BY-NC-ND 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/3.0"],["dc.title","Genetic Activation of Hedgehog Signaling Unbalances the Rate of Neural Stem Cell Renewal by Increasing Symmetric Divisions"],["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","735"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Stem Cell Reports"],["dc.bibliographiccitation.lastpage","748"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Daynac, Mathieu"],["dc.contributor.author","Tirou, Linda"],["dc.contributor.author","Faure, Helene"],["dc.contributor.author","Mouthon, Marc-Andre"],["dc.contributor.author","Gauthier, Laurent R."],["dc.contributor.author","Hahn, Heidi"],["dc.contributor.author","Boussin, Francois D."],["dc.contributor.author","Ruat, Martial"],["dc.date.accessioned","2018-11-07T10:07:06Z"],["dc.date.available","2018-11-07T10:07:06Z"],["dc.date.issued","2016"],["dc.description.abstract","Identifying the mechanisms controlling quiescence and activation of neural stem cells (NSCs) is crucial for understanding brain repair. Here, we demonstrate that Hedgehog (Hh) signaling actively regulates different pools of quiescent and proliferative NSCs in the adult ventricular-subventricular zone (V-SVZ), one of the main brain neurogenic niches. Specific deletion of the Hh receptor Patched in NSCs during adulthood upregulated Hh signaling in quiescent NSCs, progressively leading to a large accumulation of these cells in the V-SVZ. The pool of non-neurogenic astrocytes was not modified, whereas the activated NSC pool increased after a short period, before progressively becoming exhausted. We also showed that Sonic Hedgehog regulates proliferation of activated NSCs in vivo and shortens both their G1 and S-G2/M phases in culture. These data demonstrate that Hh orchestrates the balance between quiescent and activated NSCs, with important implications for understanding adult neurogenesis under normal homeostatic conditions or during injury."],["dc.identifier.doi","10.1016/j.stemcr.2016.08.016"],["dc.identifier.isi","000389508600012"],["dc.identifier.pmid","27666792"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14075"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39219"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Cell Press"],["dc.relation.issn","2213-6711"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/4.0"],["dc.title","Hedgehog Controls Quiescence and Activation of Neural Stem Cells in the Adult Ventricular-Subventricular Zone"],["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","9295"],["dc.bibliographiccitation.issue","23"],["dc.bibliographiccitation.journal","International Journal of Molecular Sciences"],["dc.bibliographiccitation.volume","21"],["dc.contributor.affiliation","Brandes, Nadine; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, nadine.brandes@med.uni-goettingen.de"],["dc.contributor.affiliation","Mitkovska, Slavica Hristomanova; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, s.hristomanovamitk@stud.uni-goettingen.de"],["dc.contributor.affiliation","Botermann, Dominik Simon; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, dominik.botermann@med.uni-goettingen.de"],["dc.contributor.affiliation","Maurer, Wiebke; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, wiebke.maurer@stud.uni-goettingen.de"],["dc.contributor.affiliation","Müllen, Anna; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, anna.muellen@stud.uni-goettingen.de"],["dc.contributor.affiliation","Scheile, Hanna; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, hannarabe@gmx.de"],["dc.contributor.affiliation","Zabel, Sebastian; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, sebastian.zabel@live.de"],["dc.contributor.affiliation","Frommhold, Anke; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, anke.frommhold@med.uni-goettingen.de"],["dc.contributor.affiliation","Heß, Ina; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, ihess@gwdg.de"],["dc.contributor.affiliation","Hahn, Heidi; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, hhahn@gwdg.de"],["dc.contributor.affiliation","Uhmann, Anja; \t\t \r\n\t\t Tumor Genetics Group, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37079 Göttingen, Germany, auhmann@gwdg.de"],["dc.contributor.author","Brandes, Nadine"],["dc.contributor.author","Mitkovska, Slavica Hristomanova"],["dc.contributor.author","Botermann, Dominik Simon"],["dc.contributor.author","Maurer, Wiebke"],["dc.contributor.author","Müllen, Anna"],["dc.contributor.author","Scheile, Hanna"],["dc.contributor.author","Zabel, Sebastian"],["dc.contributor.author","Frommhold, Anke"],["dc.contributor.author","Heß, Ina"],["dc.contributor.author","Hahn, Heidi"],["dc.contributor.author","Uhmann, Anja"],["dc.date.accessioned","2021-04-14T08:24:51Z"],["dc.date.available","2021-04-14T08:24:51Z"],["dc.date.issued","2020"],["dc.date.updated","2022-09-06T08:37:10Z"],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft"],["dc.identifier.doi","10.3390/ijms21239295"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81445"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation.eissn","1422-0067"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0/"],["dc.title","Spreading of Isolated Ptch Mutant Basal Cell Carcinoma Precursors Is Physiologically Suppressed and Counteracts Tumor Formation in Mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e61034"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Michel, Kai D."],["dc.contributor.author","Uhmann, Anja"],["dc.contributor.author","Dressel, Ralf"],["dc.contributor.author","van den Brandt, Jens"],["dc.contributor.author","Hahn, Heidi"],["dc.contributor.author","Reichardt, Holger Michael"],["dc.date.accessioned","2018-11-07T09:26:05Z"],["dc.date.available","2018-11-07T09:26:05Z"],["dc.date.issued","2013"],["dc.description.abstract","Hedgehog (Hh) signaling modulates T cell development and function but its exact role remains a matter of debate. To further address this issue we made use of conditional knock-out mice in which the Hh receptor Patched1 (Ptch) is inactivated in the T cell lineage. Thymocyte development was moderately compromised by the deletion of Ptch as characterized by reduced numbers of CD4 and CD8 single-positive cells. In contrast, peripheral T cells were not affected. Proliferation and IFN gamma secretion by Ptch-deficient T cells were indistinguishable from controls irrespectively of whether we used strong or suboptimal conditions for stimulation. Analysis of CTL and T-reg cell functions did not reveal any differences between both genotypes, and T cell apoptosis induced by glucocorticoids or gamma-irradiation was also similar. Surprisingly, absence of Ptch did not lead to an activation of canonic Hh signaling in peripheral T cells as indicated by unaltered expression levels of Gli1 and Gli2. To test whether we could uncover any role of Ptch in T cells in vivo we subjected the mutant mice to three different disease models, namely allogeneic bone marrow transplantation mimicking graft-versus-host disease, allergic airway inflammation as a model of asthma and growth of adoptively transferred melanoma cells as a means to test tumor surveillance by the immune system. Nonetheless, we were neither able to demonstrate any difference in the disease courses nor in any pathogenic parameter in these three models of adaptive immunity. We therefore conclude that the Hh receptor Ptch is dispensable for T cell function in vitro as well as in vivo."],["dc.identifier.doi","10.1371/journal.pone.0061034"],["dc.identifier.isi","000317898000092"],["dc.identifier.pmid","23577186"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/8912"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/30214"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY-NC-ND 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/3.0"],["dc.title","The Hedgehog Receptor Patched1 in T Cells Is Dispensable for Adaptive Immunity in Mice"],["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","9113"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","9124"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Nitzki, Frauke"],["dc.contributor.author","Tolosa, Ezequiel J."],["dc.contributor.author","Cuvelier, Nicole"],["dc.contributor.author","Frommhold, Anke"],["dc.contributor.author","Salinas-Riester, Gabriela"],["dc.contributor.author","Johnsen, Steven A."],["dc.contributor.author","Fernandez-Zapico, Martin E."],["dc.contributor.author","Hahn, Heidi"],["dc.date.accessioned","2019-07-09T11:41:58Z"],["dc.date.available","2019-07-09T11:41:58Z"],["dc.date.issued","2015-04-20"],["dc.description.abstract","Mice with heterozygous loss of the tumor suppressor Patched1 (Ptch) develop rhabdomyosarcoma (RMS)-like tumors. However, Ptch transcripts are consistently overexpressed in these tumors. We have recently shown that the upregulated transcripts are derived from the mutated Ptch allele thus leading to the hypothesis that the wild-type allele is repressed during RMS development. Here we describe epigenetic changes taking place at the Ptch locus during RMS development. We showed a lower degree of DNA-methylation in methylation-sensitive CpG regions of the Ptch promoter in RMS compared to normal muscle from heterozygous Ptch animals. In agreement with these results, treatment of heterozygous Ptch mice with the DNA demethylating agent 5-aza-2-deoxycytidine (5-aza-dC) between embryonic days E9.5-E11.5 significantly accelerated RMS formation. Since Ptch promoter methylation occurs after/around E13.5, the window for RMS initiation during embryogenesis, these results provide additional evidence that Ptch promoter hypomethylation may contribute to RMS formation. We have also demonstrated increased trimethylation of histone H3 lysine 4 (H3K4me3) and preferential binding of Gli1, a known Ptch activator, to the mutant locus in RMS. Together, these findings support an alternative model for RMS formation in heterozygous Ptch mice including loss of methylation and concomitant occupancy by activating histone marks of mutant Ptch."],["dc.identifier.doi","10.18632/oncotarget.3272"],["dc.identifier.pmid","25823816"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12644"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58561"],["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.title","Overexpression of mutant Ptch in rhabdomyosarcomas is associated with promoter hypomethylation and increased Gli1 and H3K4me3 occupancy."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","396"],["dc.bibliographiccitation.journal","Frontiers in Oncology"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Geyer, Natalie"],["dc.contributor.author","Ridzewski, Rosalie"],["dc.contributor.author","Bauer, Julia"],["dc.contributor.author","Kuzyakova, Maria"],["dc.contributor.author","Dittmann, Kai"],["dc.contributor.author","Dullin, Christian"],["dc.contributor.author","Rosenberger, Albert"],["dc.contributor.author","Schildhaus, Hans-Ulrich"],["dc.contributor.author","Uhmann, Anja"],["dc.contributor.author","Fulda, Simone"],["dc.contributor.author","Hahn, Heidi"],["dc.date.accessioned","2019-07-09T11:50:33Z"],["dc.date.available","2019-07-09T11:50:33Z"],["dc.date.issued","2018"],["dc.description.abstract","Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. Here we compared the therapeutic effectiveness and the impact on HH target gene expression of Smoothened (SMO) antagonists with those of the PI3K inhibitor pictilisib in ERMS with and without mutations in the HH receptor Patched1 (PTCH). Our data demonstrate that growth of ERMS showing canonical Hh signaling activity due to Ptch germline mutations is efficiently reduced by SMO antagonists. This goes along with strong downregulation of the Hh target Gli1. Likewise Ptch mutant tumors are highly responsive toward the PI3K inhibitor pictilisib, which involves modulation of AKT and caspase activity. Pictilisib also modulates Hh target gene expression, which, however, is rather not correlated with its antitumoral effects. In contrast, sporadic ERMS, which usually express HH target genes without having PTCH mutation, apparently lack canonical HH signaling activity. Thus, stimulation by Sonic HE (SHH) or SAG (Smoothened agonist) or inhibition by SMO antagonists do not modulate HH target gene expression. In addition, SMO antagonists do not provoke efficient anticancer effects and rather exert off-target effects. In contrast, pictilisib and other PI3K/AKT/mTOR inhibitors potently inhibit cellular growth. They also efficiently inhibit HH target gene expression. However, of whether this is correlated with their antitumoral effects it is not clear. Together, these data suggest that PI3K inhibitors are a good and reliable therapeutic option for all ERMS, whereas SMO inhibitors might only be beneficial for ERMS driven by PTCH mutations."],["dc.identifier.doi","10.3389/fonc.2018.00396"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15965"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59798"],["dc.language.iso","en"],["dc.subject.ddc","610"],["dc.title","Different Response of Ptch Mutant and Ptch Wildtype Rhabdomyosarcoma Toward SMO and PI3K Inhibitors"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]