Dobbelstein, Matthias

[["dc.bibliographiccitation.firstpage","780"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Cell Death and Differentiation"],["dc.bibliographiccitation.lastpage","780"],["dc.bibliographiccitation.volume","26"],["dc.contributor.author","Kramer, Daniela"],["dc.contributor.author","Stark, Nadine"],["dc.contributor.author","Schulz-Heddergott, Ramona"],["dc.contributor.author","Erytch, Norman"],["dc.contributor.author","Edmunds, Shelley"],["dc.contributor.author","Roßmann, Laura"],["dc.contributor.author","Bastians, Holger"],["dc.contributor.author","Concin, Nicole"],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2020-12-10T18:09:42Z"],["dc.date.available","2020-12-10T18:09:42Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1038/s41418-018-0190-8"],["dc.identifier.eissn","1476-5403"],["dc.identifier.issn","1350-9047"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/73731"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation.iserratumof","/handle/2/43281"],["dc.title","Correction: Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","erratum_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","275"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Journal of Experimental Medicine"],["dc.bibliographiccitation.lastpage","289"],["dc.bibliographiccitation.volume","209"],["dc.contributor.author","Schulz, Ramona"],["dc.contributor.author","Marchenko, Natalia D."],["dc.contributor.author","Holembowski, Lena"],["dc.contributor.author","Fingerle-Rowson, Guenter"],["dc.contributor.author","Pesic, Marina"],["dc.contributor.author","Zender, Lars"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T09:13:28Z"],["dc.date.available","2018-11-07T09:13:28Z"],["dc.date.issued","2012"],["dc.description.abstract","Intracellular macrophage migration inhibitory factor (MIF) often becomes stabilized in human cancer cells. MIF can promote tumor cell survival, and elevated MIF protein correlates with tumor aggressiveness and poor prognosis. However, the molecular mechanism facilitating MIF stabilization in tumors is not understood. We show that the tumor-activated HSP90 chaperone complex protects MIF from degradation. Pharmacological inhibition of HSP90 activity, or siRNA-mediated knockdown of HSP90 or HDAC6, destabilizes MIF in a variety of human cancer cells. The HSP90-associated E3 ubiquitin ligase CHIP mediates the ensuing proteasome-dependent MIF degradation. Cancer cells contain constitutive endogenous MIF-HSP90 complexes. siRNA-mediated MIF knockdown inhibits proliferation and triggers apoptosis of cultured human cancer cells, whereas HSP90 inhibitor-induced apoptosis is overridden by ectopic MIF expression. In the ErbB2 transgenic model of human HER2-positive breast cancer, genetic ablation of MIF delays tumor progression and prolongs overall survival of mice. Systemic treatment with the HSP90 inhibitor 17AAG reduces MIF expression and blocks growth of MIF-expressing, but not MIF-deficient, tumors. Together, these findings identify MIF as a novel HSP90 client and suggest that HSP90 inhibitors inhibit ErbB2-driven breast tumor growth at least in part by destabilizing MIF."],["dc.identifier.doi","10.1084/jem.20111117"],["dc.identifier.isi","000301943200009"],["dc.identifier.pmid","22271573"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10625"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/27181"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Rockefeller Univ Press"],["dc.relation.issn","0022-1007"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression"],["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","300"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Cell Death and Differentiation"],["dc.bibliographiccitation.lastpage","316"],["dc.bibliographiccitation.volume","24"],["dc.contributor.author","Kramer, Daniela"],["dc.contributor.author","Stark, Nadine"],["dc.contributor.author","Schulz-Heddergott, Ramona"],["dc.contributor.author","Erytch, Norman"],["dc.contributor.author","Edmunds, Shelley"],["dc.contributor.author","Rossmann, Laura"],["dc.contributor.author","Bastians, Holger"],["dc.contributor.author","Concin, Nicole"],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T10:27:41Z"],["dc.date.available","2018-11-07T10:27:41Z"],["dc.date.issued","2017"],["dc.description.abstract","All current regimens for treating ovarian cancer center around carboplatin as standard first line. The HSP90 inhibitor ganetespib is currently being assessed in advanced clinical oncology trials. Thus, we tested the combined effects of ganetespib and carboplatin on a panel of 15 human ovarian cancer lines. Strikingly, the two drugs strongly synergized in cytotoxicity in tumor cells lacking wild-type p53. Mechanistically, ganetespib and carboplatin in combination, but not individually, induced persistent DNA damage causing massive global chromosome fragmentation. Live-cell microscopy revealed chromosome fragmentation occurring to a dramatic degree when cells condensed their chromatin in preparation for mitosis, followed by cell death in mitosis or upon aberrant exit from mitosis. HSP90 inhibition caused the rapid decay of key components of the Fanconi anemia pathway required for repair of carboplatin-induced interstrand crosslinks (ICLs), as well as of cell cycle checkpoint mediators. Overexpressing FancA rescued the DNA damage induced by the drug combination, indicating that FancA is indeed a key client of Hsp90 that enables cancer cell survival in the presence of ICLs. Conversely, depletion of nuclease DNA2 prevented chromosomal fragmentation, pointing to an imbalance of defective repair in the face of uncontrolled nuclease activity as mechanistic basis for the observed premitotic DNA fragmentation. Importantly, the drug combination induced robust antitumor activity in xenograft models, again accompanied with depletion of FancA. In sum, our findings indicate that ganetespib strongly potentiates the antitumor efficacy of carboplatin by causing combined inhibition of DNA repair and cell cycle control mechanisms, thus triggering global chromosome disruption, aberrant mitosis and cell death."],["dc.identifier.doi","10.1038/cdd.2016.124"],["dc.identifier.isi","000395789500012"],["dc.identifier.pmid","27834954"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43281"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Nature Publishing Group"],["dc.relation.haserratum","/handle/2/73731"],["dc.relation.issn","1476-5403"],["dc.relation.issn","1350-9047"],["dc.title","Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1411"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Landmann, H."],["dc.contributor.author","Proia, D. A."],["dc.contributor.author","He, S."],["dc.contributor.author","Ogden, F. L."],["dc.contributor.author","Kramer, Franz-Josef"],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Grade, Marian"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Ghadimi, Michael B."],["dc.contributor.author","Moll, U."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T09:35:41Z"],["dc.date.available","2018-11-07T09:35:41Z"],["dc.date.issued","2014"],["dc.description.abstract","HSP90 inhibition represents a promising route to cancer therapy, taking advantage of cancer cell-inherent proteotoxic stress. The HSP90-inhibitor ganetespib showed benefit in advanced clinical trials. This raises the need to identify the molecular determinants of treatment response. We tested the efficacy of ganetespib on a series of colorectal cancer (CRC)-derived cell lines and correlated their sensitivities with comprehensive gene expression analysis. Notably, the drug concentration required for 50% growth inhibition (IC50) varied up to 70-fold (from 36 to 2500 nM) between different cell lines. Correlating cell line-specific IC(50)s with the corresponding gene expression patterns revealed a strong association between ganetespib resistance (IC50 > 500 nM) and high expression of the UDP glucuronosyltransferase 1A (UGT1A) gene cluster. Moreover, CRC tumor samples showed a comparable distribution of UGT1A expression levels. The members of the UGT1A gene family are known as drug-conjugating liver enzymes involved in drug excretion, but their function in tumor cells is hardly understood. Chemically unrelated HSP90 inhibitors, for example, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), did not show correlation of drug sensitivities with UGT1A levels, whereas the ganetespib-related compound NVP-AUY922 did. When the most ganetespib-resistant cell line, HT29, was treated with ganetespib, the levels of HSP90 clients were unaffected. However, HT29 cells became sensitized to the drug, and HSP90 client proteins were destabilized by ganetespib upon siRNA-mediated UGT1A knockdown. Conversely, the most ganetespib-sensitive cell lines HCT116 and SW480 became more tolerant toward ganetespib upon UGT1A overexpression. Mechanistically, ganetespib was rapidly glucuronidated and excreted in resistant but not in sensitive CRC lines. We conclude that CRC cell-expressed UGT1A inactivates ganetespib and other resorcinolic Hsp90 inhibitors by glucuronidation, which renders the drugs unable to inhibit Hsp90 and thereby abrogates their biological activity. UGT1A levels in tumor tissues may be a suitable predictive biomarker to stratify CRC patients for ganetespib treatment."],["dc.description.sponsorship","Open-Access Publikationsfonds 2014"],["dc.identifier.doi","10.1038/cddis.2014.378"],["dc.identifier.isi","000343162000012"],["dc.identifier.pmid","25210794"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10891"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/32445"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY-NC-ND 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/3.0"],["dc.title","UDP glucuronosyltransferase 1A expression levels determine the response of colorectal cancer cells to the heat shock protein 90 inhibitor ganetespib"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","398"],["dc.bibliographiccitation.issue","7578"],["dc.bibliographiccitation.journal","Nature"],["dc.bibliographiccitation.lastpage","398"],["dc.bibliographiccitation.volume","527"],["dc.contributor.author","Alexandrova, E. M."],["dc.contributor.author","Yallowitz, A. R."],["dc.contributor.author","Li, D."],["dc.contributor.author","Xu, S."],["dc.contributor.author","Schulz, R."],["dc.contributor.author","Proia, D. A."],["dc.contributor.author","Lozano, G."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Moll, U. M."],["dc.date.accessioned","2022-03-01T11:45:50Z"],["dc.date.available","2022-03-01T11:45:50Z"],["dc.date.issued","2015"],["dc.identifier.doi","10.1038/nature15720"],["dc.identifier.pii","BFnature15720"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103468"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1476-4687"],["dc.relation.iserratumof","/handle/2/36569"],["dc.relation.isformatof","/handle/2/36569"],["dc.relation.issn","0028-0836"],["dc.rights.uri","http://www.springer.com/tdm"],["dc.title","Erratum: Corrigendum: Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","erratum_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","10094"],["dc.bibliographiccitation.issue","24"],["dc.bibliographiccitation.journal","Cancer Research"],["dc.bibliographiccitation.lastpage","10104"],["dc.bibliographiccitation.volume","68"],["dc.contributor.author","Braun, Christian J."],["dc.contributor.author","Zhang, X."],["dc.contributor.author","Savelyeva, Irina"],["dc.contributor.author","Wolff, Sonja"],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Schepeler, Troels"],["dc.contributor.author","Orntoft, Torben F."],["dc.contributor.author","Andersen, Claus L."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T11:07:54Z"],["dc.date.available","2018-11-07T11:07:54Z"],["dc.date.issued","2008"],["dc.description.abstract","microRNAs provide a novel layer of regulation for gene expression by interfering with the stability and/or translation of specific target mRNAs. Overall levels of microRNTAs are frequently down-regulated in cancer cells, and reducing general microRNA processing increases cancerogenesis in transgenic models, suggesting that at least some microRNAs might act as effectors in tumor suppression. Accordingly, the tumor suppressor p53 up-regulates miR-34a, a microR-NtA that contributes to apoptosis and acute senescence. Here, we used array hybridization to rind that p53 induces two additional, mutually related clusters of microRNAs, leading to the up-regulation of miR-192, miR-194, and miR-215. The same microRNAs were detected at high levels in normal colon tissue but were severely reduced in many colon cancer samples. On the other hand, miR-192 and its cousin miR-215 can each contribute to enhanced CDKN1A/p21 levels, colony suppression, cell cycle arrest, and cell detachment from a solid support. These effects were partially dependent on the presence of wild-type p53. Antagonizing endogenous miR-192 attenuated 5-fluorouracil-induced accumulation of p21. Hence, miR-192 and miR-215 can act as effectors as well as regulators of p53; they seem to suppress cancerogenesis through p21 accumulation and cell cycle arrest. [Cancer Res 2008;68(24):10094-104]"],["dc.description.sponsorship","NCI NIH HHS [R01 CA060664, R01 CA060664-13]"],["dc.identifier.doi","10.1158/0008-5472.CAN-08-1569"],["dc.identifier.isi","000261866800013"],["dc.identifier.pmid","19074875"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6279"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/52681"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Assoc Cancer Research"],["dc.relation.issn","0008-5472"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","p53-Responsive MicroRNAs 192 and 215 Are Capable of Inducing Cell Cycle Arrest"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","352"],["dc.bibliographiccitation.issue","7560"],["dc.bibliographiccitation.journal","Nature"],["dc.bibliographiccitation.lastpage","+"],["dc.bibliographiccitation.volume","523"],["dc.contributor.author","Alexandrova, Evguenia M."],["dc.contributor.author","Yallowitz, A. R."],["dc.contributor.author","Li, D."],["dc.contributor.author","Xu, S."],["dc.contributor.author","Schulz, R."],["dc.contributor.author","Proia, D. A."],["dc.contributor.author","Lozano, G."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T09:54:36Z"],["dc.date.available","2018-11-07T09:54:36Z"],["dc.date.issued","2015"],["dc.description.abstract","Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance(1-5). Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities(6-8). Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo. Here we use a novel mutp53 mouse model expressing an inactivatable R248Q hotspot mutation (floxQ) to show that tumours depend on sustained mutp53 expression. Upon tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation. The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization(9-12). We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/- (R248Q allele(2)) and H/H (R172H allele(3)) mice by 59% and 48%, respectively, but not their corresponding p53(-/-) (also known as Trp53(-/-)) littermates. This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/- mice treated with the potent Hsp90 inhibitor ganetespib. Notably, drug activity correlates with induction of mutp53 degradation, tumour apoptosis and prevention of T-cell lymphomagenesis. These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target."],["dc.identifier.doi","10.1038/nature14430"],["dc.identifier.isi","000357950900043"],["dc.identifier.pmid","26009011"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/36569"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.haserratum","/handle/2/103468"],["dc.relation.issn","1476-4687"],["dc.relation.issn","0028-0836"],["dc.title","Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e980"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Schulz, R."],["dc.contributor.author","Streller, F."],["dc.contributor.author","Scheel, Andreas Hans"],["dc.contributor.author","Rueschoff, Josef"],["dc.contributor.author","Reinert, M. C."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Marchenko, N. D."],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T09:46:24Z"],["dc.date.available","2018-11-07T09:46:24Z"],["dc.date.issued","2014"],["dc.description.abstract","Overexpression of the human epidermal growth factor receptor-2 (HER2) in breast cancer strongly correlates with aggressive tumors and poor prognosis. Recently, a positive correlation between HER2 and MIF (macrophage migration inhibitory factor, a tumor-promoting protein and heat-shock protein 90 (HSP90) client) protein levels was shown in cancer cells. However, the underlying mechanistic link remained unknown. Here we show that overexpressed HER2 constitutively activates heat-shock factor 1 (HSF1), the master transcriptional regulator of the inducible proteotoxic stress response of heat-shock chaperones, including HSP90, and a crucial factor in initiation and maintenance of the malignant state. Inhibiting HER2 pharmacologically by Lapatinib (a dual HER2/epidermal growth factor receptor inhibitor) or CP724.714 (a specific HER2 inhibitor), or by knockdown via siRNA leads to inhibition of phosphoactivated Ser326 HSF1, and subsequently blocks the activity of the HSP90 chaperone machinery in HER2-overexpressing breast cancer lines. Consequently, HSP90 clients, including MIF, AKT, mutant p53 and HSF1 itself, become destabilized, which in turn inhibits tumor proliferation. Mechanistically, HER2 signals via the phosphoinositide-3kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis to induce activated pSer326 HSF1. Heat-shock stress experiments confirm this functional link between HER2 and HSF1, as HER2 (and PI3K) inhibition attenuate the HSF1-mediated heat-shock response. Importantly, we confirmed this axis in vivo. In the mouse model of HER2-driven breast cancer, ErbB2 inhibition by Lapatinib strongly suppresses tumor progression, and this is associated with inactivation of the HSF1 pathway. Moreover, ErbB2-overexpressing cancer cells derived from a primary mouse ErbB2 tumor also show HSF1 inactivation and HSP90 client destabilization in response to ErbB2 inhibition. Furthermore, in HER2-positive human breast cancers HER2 levels strongly correlate with pSer326 HSF1 activity. Our results show for the first time that HER2/ErbB2 overexpression controls HSF1 activity, with subsequent stabilization of numerous tumor-promoting HSP90 clients such as MIF, AKT and HSF1 itself, thereby causing a robust promotion in tumor growth in HER2-positive breast cancer."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2014"],["dc.identifier.doi","10.1038/cddis.2013.508"],["dc.identifier.isi","000332222700004"],["dc.identifier.pmid","24384723"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/9556"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34861"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY-NC-SA 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-sa/3.0"],["dc.title","HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer"],["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","3624"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Proceedings of the National Academy of Sciences of the United States of America"],["dc.bibliographiccitation.lastpage","3629"],["dc.bibliographiccitation.volume","108"],["dc.contributor.author","Beyer, Ulrike"],["dc.contributor.author","Moll-Rocek, Julian"],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T08:58:47Z"],["dc.date.available","2018-11-07T08:58:47Z"],["dc.date.issued","2011"],["dc.description.abstract","TAp63, but not its homolog p53, eliminates oocytes that suffered DNA damage. An equivalent gene for guarding the male germ line is currently not known. Here we identify hitherto unknown human p63 transcripts with unique 5'-ends derived from incorporated exons upstream of the currently mapped TP63 gene. These unique p63 transcripts are highly and specifically expressed in testis. Their most upstream region corresponds to a LTR of the human endogenous retrovirus 9 (ERV9). The insertion of this LTR upstream of the TP63 locus occurred only recently in evolution and is unique to humans and great apes (Hominidae). A corresponding p63 protein is the sole p63 species in healthy human testis, and is strongly expressed in spermatogenic precursors but not in mature spermatozoa. In response to DNA damage, this human male germ-cell-encoded TAp63 protein (designated GTAp63) is activated by caspase cleavage near its carboxyterminal domain and induces apoptosis. Human testicular cancer tissues and cell lines largely lost p63 expression. However, pharmacological inhibition of histone deacetylases completely restores p63 expression in testicular cancer cells (> 3,000-fold increase). Our data support a model whereby testis-specific GTAp63 protects the genomic integrity of the male germ line and acts as a tumor suppressor. In Hominidae, this guardian function was greatly enhanced by integration of an endogenous retrovirus upstream of the TP63 locus that occurred 15 million years ago. By providing increased germ-line stability, this event may have contributed to the evolution of hominids and enabled their long reproductive periods."],["dc.identifier.doi","10.1073/pnas.1016201108"],["dc.identifier.isi","000287844400037"],["dc.identifier.pmid","21300884"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/23727"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Natl Acad Sciences"],["dc.relation.issn","0027-8424"],["dc.title","Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","243"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Molecular Cell"],["dc.bibliographiccitation.lastpage","257"],["dc.bibliographiccitation.volume","59"],["dc.contributor.author","Zhang, X."],["dc.contributor.author","Schulz, Ramona"],["dc.contributor.author","Edmunds, Shelley"],["dc.contributor.author","Krueger, Elke"],["dc.contributor.author","Markert, Elke"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Cormet-Boyaka, Estelle"],["dc.contributor.author","Ghadimi, Michael B."],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Levine, Arnold J."],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T09:54:34Z"],["dc.date.available","2018-11-07T09:54:34Z"],["dc.date.issued","2015"],["dc.description.abstract","Proteasome inhibition represents a promising strategy of cancer pharmacotherapy, but resistant tumor cells often emerge. Here we show that the micro-RNA-101 (miR-101) targets the proteasome maturation protein POMP, leading to impaired proteasome assembly and activity, and resulting in accumulation of p53 and cyclin-dependent kinase inhibitors, cell cycle arrest, and apoptosis. miR-101-resistant POMP restores proper turnover of proteasome substrates and re-enables tumor cell growth. In ER alpha-positive breast cancers, miR-101 and POMP levels are inversely correlated, and high miR-101 expression or low POMP expression associates with prolonged survival. Mechanistically, miR-101 expression or POMP knockdown attenuated estrogen-driven transcription. Finally, suppressing POMP is sufficient to overcome tumor cell resistance to the proteasome inhibitor bortezomib. Taken together, proteasome activity can not only be manipulated through drugs, but is also subject to endogenous regulation through miR-101, which targets proteasome biogenesis to control overall protein turnover and tumor cell proliferation."],["dc.identifier.doi","10.1016/j.molcel.2015.05.036"],["dc.identifier.isi","000362457000012"],["dc.identifier.pmid","26145175"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/36564"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Cell Press"],["dc.relation.issn","1097-4164"],["dc.relation.issn","1097-2765"],["dc.title","MicroRNA-101 Suppresses Tumor Cell Proliferation by Acting as an Endogenous Proteasome Inhibitor via Targeting the Proteasome Assembly Factor POMP"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]