Dobbelstein, Matthias

[["dc.bibliographiccitation.firstpage","1426"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Cell Cycle"],["dc.bibliographiccitation.lastpage","1432"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Scheel, Andreas Hans Joachim"],["dc.contributor.author","Beyer, Ulrike"],["dc.contributor.author","Agami, Reuven"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T08:30:11Z"],["dc.date.available","2018-11-07T08:30:11Z"],["dc.date.issued","2009"],["dc.description.abstract","The tumor suppressor homologue p63 is required for proper skin and limb development, but specific isoforms of it also act as a \"guardian of the germline.\" To gain insight into the regulation of p63 expression, we performed immunofluorescence-based screening assays. Using a large collection of microRNA expression plasmids, we identified microRNAs of the 302 cluster as potent suppressors of p63 accumulation in various cell species. MiR-302 reduces p63 protein and mRNA levels through two target sites within the p63 3' untranslated region. In testicular cancer cells, endogenous miR-302 contributes to the suppression of p63. MiR-302 might also contribute to the elimination of p63 in mature oocytes. Thus, miR-302 appears as part of a stringent regulatory mechanism for p63 in germ cells, reminiscent of the tight control for p53 levels in somatic cells."],["dc.identifier.doi","10.4161/cc.8.9.8324"],["dc.identifier.isi","000266114600030"],["dc.identifier.pmid","19342891"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/16831"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Landes Bioscience"],["dc.relation.issn","1538-4101"],["dc.title","Immunofluorescence-based screening identifies germ cell associated microRNA 302 as an antagonist to p63 expression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["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","64"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Cell Death and Differentiation"],["dc.bibliographiccitation.lastpage","75"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Beyer, Ulrike"],["dc.contributor.author","Kroenung, S. K."],["dc.contributor.author","Leha, Andreas"],["dc.contributor.author","Walter, L."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T10:21:23Z"],["dc.date.available","2018-11-07T10:21:23Z"],["dc.date.issued","2016"],["dc.description.abstract","The long terminal repeat (LTR) of human endogenous retrovirus type 9 (ERV9) acts as a germline-specific promoter that induces the expression of a proapoptotic isoform of the tumor suppressor homologue p63, GTAp63, in male germline cells. Testicular cancer cells silence this promoter, but inhibitors of histone deacetylases (HDACs) restore GTAp63 expression and give rise to apoptosis. We show here that numerous additional transcripts throughout the genome are driven by related ERV9-LTRs. 3'Rapid amplification of cDNA ends (3'RACE) was combined with next-generation sequencing to establish a large set of such mRNAs. HDAC inhibitors induce these ERV9-LTR-driven genes but not the LTRs from other ERVs. In particular, a transcript encoding the death receptor DR5 originates from an ERV9-LTR inserted upstream of the protein coding regions of the TNFRSF10B gene, and it shows an expression pattern similar to GTAp63. When treating testicular cancer cells with HDAC inhibitors as well as the death ligand TNF-related apoptosis-inducing ligand (TRAIL), rapid cell death was observed, which depended on TNFRSF10B expression. HDAC inhibitors also cooperate with cisplatin (cDDP) to promote apoptosis in testicular cancer cells. ERV9-LTRs not only drive a large set of human transcripts, but a subset of them acts in a proapoptotic manner. We propose that this avoids the survival of damaged germ cells. HDAC inhibition represents a strategy of restoring the expression of a class of ERV9-LTR-mediated genes in testicular cancer cells, thereby re-enabling tumor suppression."],["dc.identifier.doi","10.1038/cdd.2015.68"],["dc.identifier.isi","000368062000017"],["dc.identifier.pmid","26024393"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42072"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","1476-5403"],["dc.relation.issn","1350-9047"],["dc.title","Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1108"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Cell Death and Differentiation"],["dc.bibliographiccitation.lastpage","1117"],["dc.bibliographiccitation.volume","16"],["dc.contributor.author","Wolff, S."],["dc.contributor.author","Talos, Flaminia"],["dc.contributor.author","Palacios, Gustavo"],["dc.contributor.author","Beyer, Ulrike"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T11:25:53Z"],["dc.date.available","2018-11-07T11:25:53Z"],["dc.date.issued","2009"],["dc.description.abstract","p63, an ancestral transcription factor of the p53 family, has three C-terminal isoforms whose relative in vivo functions are elusive. The p63 gene is essential for skin and limb development, as vividly shown by two independent global knockout mouse models. Both strains, although constructed differently, have identical and severe phenotypes, characterized by absent epidermis and hindlimbs and only rudimentary forelimbs at birth. Here we show that mice from one model, Brdm2, express normal levels of truncated p63 proteins that contain the DNA binding and oligomerization domain but lack the long carboxy-terminal SAM (sterile alpha-motif) and post-SAM domains that are specific for the alpha and beta isoforms. As such, transcriptionally active p63 proteins from Brdm2 mice resemble the naturally occurring p63 gamma isoforms, which of all the p63 isoforms most closely resemble p53. Thus, Brdm2 mice are p63 alpha/beta isoform-specific knockout mice, gaining unexpected new importance. Our studies identify that p63 alpha/beta but not p63 gamma are absolutely required for proper skin and limb development. Cell Death and Differentiation (2009) 16, 1108-1117; doi:10.1038/cdd.2009.25; published online 20 March 2009"],["dc.identifier.doi","10.1038/cdd.2009.25"],["dc.identifier.isi","000267948900005"],["dc.identifier.pmid","19300453"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/56726"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","1350-9047"],["dc.title","The alpha/beta carboxy-terminal domains of p63 are required for skin and limb development. New insights from the Brdm2 mouse which is not a complete p63 knockout but expresses p63 gamma-like proteins"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1905"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Cell Cycle"],["dc.bibliographiccitation.lastpage","1911"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Beyer, Ulrike"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T08:55:03Z"],["dc.date.available","2018-11-07T08:55:03Z"],["dc.date.issued","2011"],["dc.description.abstract","We have recently identified novel isoforms of human p63, with specific expression in testicular germ cells. The synthesis of these p63 mRNA species is driven by the long terminal repeat (LTR) of the endogenous retrovirus ERV9. This LTR was inserted upstream of the previously known TP63 exons roughly 15 million years ago, leading to the expression of novel exons and the synthesis of germline-specific transactivating p63 (GTAp63) isoforms in humans and great apes (Beyer et al. Proc Natl Acad Sci USA 2011; 108: 3624-9). However, this study did not reveal whether similar upstream exons can also be found in the TP63 genes of non-hominid animals. Here we performed rapid amplification of cDNA ends (RACE) to identify a novel upstream exon of murine TP63, located in 5' position from the previously described start of transcription. This exon, termed \"exon U3\" in our previous publication, is conserved within a broad range of mammalian species, including hominids. However, in contrast to the human TP63 gene structure, the murine exon U3 represented the most upstream transcribed sequence of TP63. Murine exon U3 is then alternatively spliced to acceptor sites within exon 1 or upstream of exon 2, resulting in two different available translational start sites. p63 mRNAs comprising exon U3 are detectable in various tissues, with no particular preference for testicular cells. Thus, whereas the retroviral LTR in hominid species results in strictly germline-associated p63 isoforms, the upstream exon in non-hominids fails to confer this tissue specificity. This notion strongly supports the concept that the synthesis of a testis-specific p63 isoform is a recently acquired, unique feature of humans and great apes."],["dc.identifier.doi","10.4161/cc.10.12.15838"],["dc.identifier.isi","000291651300013"],["dc.identifier.pmid","21558811"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/22815"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Landes Bioscience"],["dc.relation.issn","1538-4101"],["dc.title","Non-hominid TP63 lacks retroviral LTRs but contains a novel conserved upstream exon"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","184"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Cell Death and Differentiation"],["dc.bibliographiccitation.lastpage","186"],["dc.bibliographiccitation.volume","17"],["dc.contributor.author","Talos, Flaminia"],["dc.contributor.author","Wolff, S."],["dc.contributor.author","Beyer, Ulrike"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T08:47:15Z"],["dc.date.available","2018-11-07T08:47:15Z"],["dc.date.issued","2010"],["dc.description.sponsorship","NCI NIH HHS [R01 CA093853, R01 CA093853-07]"],["dc.identifier.doi","10.1038/cdd.2009.158"],["dc.identifier.isi","000272818700021"],["dc.identifier.pmid","20161489"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/20904"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","1350-9047"],["dc.title","Brdm2-an aberrant hypomorphic p63 allele"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.subtype","letter_note"],["dspace.entity.type","Publication"]]