@article{SchmittBackesNourkamiTutdibietal.2012, author = {Schmitt, Jana and Backes, Christina and Nourkami-Tutdibi, Nasenien and Leidinger, Petra and Deutscher, Stephanie and Beier, Markus and Gessler, Manfred and Graf, Norbert and Lenhof, Hans-Peter and Keller, Andreas and Meese, Eckart}, title = {Treatment-independent miRNA signature in blood of wilms tumor patients}, series = {BMC Genomics}, volume = {13}, journal = {BMC Genomics}, number = {379}, doi = {10.1186/1471-2164-13-379}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124034}, year = {2012}, abstract = {Background Blood-born miRNA signatures have recently been reported for various tumor diseases. Here, we compared the miRNA signature in Wilms tumor patients prior and after preoperative chemotherapy according to SIOP protocol 2001. Results We did not find a significant difference between miRNA signature of both groups. However both, Wilms tumor patients prior and after chemotherapy showed a miRNA signature different from healthy controls. The signature of Wilms tumor patients prior to chemotherapy showed an accuracy of 97.5\% and of patients after chemotherapy an accuracy of 97.0\%, each as compared to healthy controls. Conclusion Our results provide evidence for a blood-born Wilms tumor miRNA signature largely independent of four weeks preoperative chemotherapy treatment.}, language = {en} } @article{WegertVokuhZiegleretal.2017, author = {Wegert, Jenny and Vokuh, Christian and Ziegler, Barbara and Ernestus, Karen and Leuschner, Ivo and Furtw{\"a}ngler, Rhoikos and Graf, Norbert and Gessler, Manfred}, title = {TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia}, series = {The Journal of Pathology: Clinical Research}, volume = {3}, journal = {The Journal of Pathology: Clinical Research}, doi = {10.1002/cjp2.77}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158302}, pages = {234-248}, year = {2017}, abstract = {TP53 mutations have been associated with anaplasia in Wilms tumour, which conveys a high risk for relapse and fatal outcome. Nevertheless, TP53 alterations have been reported in no more than 60\% of anaplastic tumours, and recent data have suggested their presence in tumours that do not fulfil the criteria for anaplasia, questioning the clinical utility of TP53 analysis. Therefore, we characterized the TP53 status in 84 fatal cases of Wilms tumour, irrespective of histological subtype. We identified TP53 alterations in at least 90\% of fatal cases of anaplastic Wilms tumour, and even more when diffuse anaplasia was present, indicating a very strong if not absolute coupling between anaplasia and deregulation of p53 function. Unfortunately, TP53 mutations do not provide additional predictive value in anaplastic tumours since the same mutation rate was found in a cohort of non-fatal anaplastic tumours. When classified according to tumour stage, patients with stage I diffuse anaplastic tumours still had a high chance of survival (87\%), but this rate dropped to 26\% for stages II-IV. Thus, volume of anaplasia or possible spread may turn out to be critical parameters. Importantly, among non-anaplastic fatal tumours, 26\% had TP53 alterations, indicating that TP53 screening may identify additional cases at risk. Several of these non-anaplastic tumours fulfilled some criteria for anaplasia, for example nuclear unrest, suggesting that such partial phenotypes should be under special scrutiny to enhance detection of high-risk tumours via TP53 screening. A major drawback is that these alterations are secondary changes that occur only later in tumour development, leading to striking intratumour heterogeneity that requires multiple biopsies and analysis guided by histological criteria. In conclusion, we found a very close correlation between histological signs of anaplasia and TP53 alterations. The latter may precede development of anaplasia and thereby provide diagnostic value pointing towards aggressive disease.}, language = {en} } @article{GesslerGrupeGrzeschiketal.1992, author = {Gessler, Manfred and Grupe, Andrew and Grzeschik, Karl-Heinz and Pongs, Olaf}, title = {The potassium channel gene HK1 maps to human chromosome 11p14.1, close to the FSHB gene}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59184}, year = {1992}, abstract = {Transiently activating (A-type) potassium (K) channels are important regulators of action potential and action potential firing frequencies. HK1 designates the firsthuman cDNA that is highly homologous to the rat RCK4 cDNA that codes for an A-type K-channel. The HK1 channel is expressed in heart. By somatic cell hybrid analysis, the HK1 gene has been assigned to human chromosome 11p13-pl4, the WAGR deletion region (Wilms tumor, aniridia, genito-urinary abnormalities and mental retardation). Subsequent pulsed field gel (PFG) analysis and comparison with the well-established PFG map of this region localized the gene to 11p14, 200-600 kb telomeric to the FSHB gene.}, subject = {Biochemie}, language = {en} } @article{GesslerHameisterHenryetal.1990, author = {Gessler, Manfred and Hameister, H. and Henry, I. and Junien, C. and Braun, T. and Arnold, H. H.}, title = {The human MyoD1 (MYF3) gene maps on the short arm of chromosome 11 but is not associated with the WAGR locus or the region for the Beckwith-Wiedemann syndrome}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59221}, year = {1990}, abstract = {The human gene encoding the myogenic determination factor myf3 (mouse MyoD1) has been mapped to the short arm of chromosome 11. Analysis of several somatic cell hybrids containing various derivatives with deletions or translocations revealed that the human MyoD (MYF3) gene is not associated with the WAGR locus at chromosomal band 11pl3 nor with the loss of the heterozygosity region at 11p15.5 related to the Beckwith-Wiedemann syndrome. Subregional mapping by in situ hybridization with an myf3 specific probe shows that the gene resides at the chromosomal band llp14, possibly at llp14.3.}, subject = {Biochemie}, language = {en} } @article{GesslerKoenigBruns1992, author = {Gessler, Manfred and K{\"o}nig, A. and Bruns, G. A. P.}, title = {The genomic organization and expression of the WT1 gene}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59195}, year = {1992}, abstract = {The Wilms tumor gene WTl, a proposed tumor suppressor gene, has been identifled based on its location within a homozygous deletion found in tumor tissue. The gene encodes a putative transcription factor containing a Cys/His zinc finger domain. The critical homozygous deletions, however, are rarely seen, suggesting that in many cases the gene may be inactivated by more subtle alterations. To facilitate the seareh for smaller deletions and point mutations we have established the genomic organization of the WTl gene and have determined the sequence of all 10 exons and flanking intron DNA. The pattern of alternative splicing in two regions has been characterized in detail. These results will form the basis for future studies of mutant alleles at this locus.}, subject = {Biochemie}, language = {en} } @article{HeisigWeberEnglbergeretal.2012, author = {Heisig, Julia and Weber, David and Englberger, Eva and Winkler, Anja and Kneitz, Susanne and Sung, Wing-Kin and Wolf, Elmar and Eilers, Martin and Wei, Chia-Lin and Gessler, Manfred}, title = {Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH Repressors}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75341}, year = {2012}, abstract = {HEY bHLH transcription factors have been shown to regulate multiple key steps in cardiovascular development. They can be induced by activated NOTCH receptors, but other upstream stimuli mediated by TGFß and BMP receptors may elicit a similar response. While the basic and helix-loop-helix domains exhibit strong similarity, large parts of the proteins are still unique and may serve divergent functions. The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells. We therefore sought to identify target genes for HEY proteins by microarray expression and ChIPseq analyses in HEK293 cells, cardiomyocytes, and murine hearts. HEY proteins were found to modulate expression of their target gene to a rather limited extent, but with striking functional interchangeability between HEY factors. Chromatin immunoprecipitation revealed a much greater number of potential binding sites that again largely overlap between HEY factors. Binding sites are clustered in the proximal promoter region especially of transcriptional regulators or developmental control genes. Multiple lines of evidence suggest that HEY proteins primarily act as direct transcriptional repressors, while gene activation seems to be due to secondary or indirect effects. Mutagenesis of putative DNA binding residues supports the notion of direct DNA binding. While class B E-box sequences (CACGYG) clearly represent preferred target sequences, there must be additional and more loosely defined modes of DNA binding since many of the target promoters that are efficiently bound by HEY proteins do not contain an Ebox motif. These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression.}, subject = {Biologie}, language = {en} } @misc{GesslerBruns1993, author = {Gessler, Manfred and Bruns, Gail A.}, title = {Sequence of the WT1 upstream region including the Wit-1 gene}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-30193}, year = {1993}, abstract = {No abstract available}, language = {en} } @article{vanHeyningenBickmoreSeawrightetal.1990, author = {van Heyningen, V. and Bickmore, W. A. and Seawright, A. and Fletcher, J. M. and Maule, J. and Fekete, G. and Gessler, Manfred and Bruns, G. A. and Huerre-Jeanpierre, C. and Junien, C.}, title = {Role for the Wilms tumor gene in genital development?}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59238}, year = {1990}, abstract = {No abstract available}, subject = {Biochemie}, language = {en} } @article{WegertBausenweinKneitzetal.2011, author = {Wegert, Jenny and Bausenwein, Sabrina and Kneitz, Susanne and Roth, Sabine and Graf, Norbert and Geissinger, Eva and Gessler, Manfred}, title = {Retinoic acid pathway activity in Wilms tumors and characterization of biological responses in vitro}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69137}, year = {2011}, abstract = {Background: Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90\% of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear. Results: The association of retinoid signaling and clinical parameters could be validated in a large independent tumor set, but its relevance in primary nephrectomy tumors from very young children may be different. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/ intermediate risk, suggesting a beneficial impact of RA especially on advanced WT. To search for possible modes of action of retinoids as novel therapeutic options, primary tumor cell cultures were treated in vitro with all-trans-RA (ATRA), 9cis-RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid/HDAC inhibitor combinations provided no synergistic effect. ATRA and 9cis-RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. The effects documented appear to be reversible upon drug withdrawal, however. Conclusions: Altered retinoic acid signaling has been validated especially in high risk Wilms tumors. In vitro testing of primary tumor cultures provided clear evidence of a potential utility of retinoids in Wilms tumor treatment based on the analysis of gene expression, proliferation, differentiation and apoptosis.}, subject = {Krebs}, language = {en} } @article{TuChenLimetal.2012, author = {Tu, Xiaolin and Chen, Jianquan and Lim, Joohyun and Karner, Courtney M. and Lee, Seung-Yon and Heisig, Julia and Wiese, Cornelia and Surendran, Kameswaran and Kopan, Raphael and Gessler, Manfred and Long, Fanxin}, title = {Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1}, series = {PLoS Genetics}, volume = {8}, journal = {PLoS Genetics}, number = {3}, doi = {10.1371/journal.pgen.1002577}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133490}, pages = {e1002577}, year = {2012}, abstract = {Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo.}, language = {en} }