@article{BartlScholzHinterbergeretal.2011, author = {Bartl, Jasmin and Scholz, Claus-J{\"u}rgen and Hinterberger, Margareta and Jungwirth, Susanne and Wichart, Ildiko and Rainer, Michael K. and Kneitz, Susanne and Danielczyk, Walter and Tragl, Karl H. and Fischer, Peter and Riederer, Peter and Gr{\"u}nblatt, Edna}, title = {Disorder-specific effects of polymorphisms at opposing ends of the Insulin Degrading Enzymegene}, series = {BMC Medical Genetics}, volume = {12}, journal = {BMC Medical Genetics}, number = {151}, doi = {10.1186/1471-2350-12-15}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137744}, year = {2011}, abstract = {Background Insulin-degrading enzyme (IDE) is the ubiquitously expressed enzyme responsible for insulin and amyloid beta (Aβ) degradation. IDE gene is located on chromosome region 10q23-q25 and exhibits a well-replicated peak of linkage with Type 2 diabetes mellitus (T2DM). Several genetic association studies examined IDE gene as a susceptibility gene for Alzheimer's disease (AD), however with controversial results. Methods We examined associations of three IDE polymorphisms (IDE2, rs4646953; IDE7, rs2251101 and IDE9, rs1887922) with AD, Aβ42 plasma level and T2DM risk in the longitudinal Vienna Transdanube Aging (VITA) study cohort. Results The upstream polymorphism IDE2 was found to influence AD risk and to trigger the Aβ42 plasma level, whereas the downstream polymorphism IDE7 modified the T2DM risk; no associations were found for the intronic variant IDE9. Conclusions Based on our SNP and haplotype results, we delineate the model that IDE promoter and 3' untranslated region/downstream variation may have different effects on IDE expression, presumably a relevant endophenotype with disorder-specific effects on AD and T2DM susceptibility.}, language = {en} } @article{HuangBelharazemLietal.2013, author = {Huang, Bei and Belharazem, Djeda and Li, Li and Kneitz, Susanne and Schnabel, Philipp A. and Rieker, Ralf J. and K{\"o}rner, Daniel and Nix, Wilfried and Schalke, Berthold and M{\"u}ller-Hermelink, Hans Konrad and Ott, German and Rosenwald, Andreas and Str{\"o}bel, Philipp and Marx, Alexander}, title = {Anti-apoptotic signature in thymic squamous cell carcinomas - functional relevance of anti-apoptotic BIRC3 expression in the thymic carcinoma cell line 1889c}, series = {Frontiers in Oncology}, volume = {3}, journal = {Frontiers in Oncology}, number = {316}, doi = {10.3389/fonc.2013.00316}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132214}, year = {2013}, abstract = {The molecular pathogenesis of thymomas and thymic arcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important.This made us re-analyze historic expression data obtained in a spectrumof thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC.}, language = {en} } @article{VandenHoveJakobSchrautetal.2011, author = {Van den Hove, Daniel and Jakob, Sissi Brigitte and Schraut, Karla-Gerlinde and Kenis, Gunter and Schmitt, Angelika Gertrud and Kneitz, Susanne and Scholz, Claus-J{\"u}rgen and Wiescholleck, Valentina and Ortega, Gabriela and Prickaerts, Jos and Steinbusch, Harry and Lesch, Klaus-Peter}, title = {Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene x Environment Interactions}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0022715}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135111}, pages = {e22715}, year = {2011}, abstract = {Prenatal stress (PS) has been shown to influence the development of the fetal brain and to increase the risk for the development of psychiatric disorders in later life. Furthermore, the variation of human serotonin transporter (5-HTT, SLC6A4) gene was suggested to exert a modulating effect on the association between early life stress and the risk for depression. In the present study, we used a 5-HttxPS paradigm to investigate whether the effects of PS are dependent on the 5-Htt genotype. For this purpose, the effects of PS on cognition, anxiety-and depression-related behavior were examined using a maternal restraint stress paradigm of PS in C57BL6 wild-type (WT) and heterozygous 5-Htt deficient (5-Htt +/-) mice. Additionally, in female offspring, a genome-wide hippocampal gene expression profiling was performed using the Affymetrix GeneChip (R) Mouse Genome 430 2.0 Array. 5-Htt +/- offspring showed enhanced memory performance and signs of reduced anxiety as compared to WT offspring. In contrast, exposure of 5-Htt +/- mice to PS was associated with increased depressive-like behavior, an effect that tended to be more pronounced in female offspring. Further, 5-Htt genotype, PS and their interaction differentially affected the expression of numerous genes and related pathways within the female hippocampus. Specifically, MAPK and neurotrophin signaling were regulated by both the 5-Htt +/- genotype and PS exposure, whereas cytokine and Wnt signaling were affected in a 5-Htt genotypexPS manner, indicating a genexenvironment interaction at the molecular level. In conclusion, our data suggest that although the 5-Htt +/- genotype shows clear adaptive capacity, 5-Htt +/- mice -particularly females-at the same time appear to be more vulnerable to developmental stress exposure when compared to WT offspring. Moreover, hippocampal gene expression profiles suggest that distinct molecular mechanisms mediate the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction.}, language = {en} } @article{RiedelMofoloAvotaetal.2013, author = {Riedel, Alice and Mofolo, Boitumelo and Avota, Elita and Schneider-Schaulies, Sibylle and Meintjes, Ayton and Mulder, Nicola and Kneitz, Susanne}, title = {Accumulation of Splice Variants and Transcripts in Response to PI3K Inhibition in T Cells}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {2}, doi = {10.1371/journal.pone.0050695}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130335}, pages = {e50695}, year = {2013}, abstract = {Background Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Hypothesis Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. Methods To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. Results Applying our algorithm to the data, 9\% of the genes were assigned as AS, while only 3\% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. Conclusions PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.}, language = {en} } @article{VerghoKneitzKalogirouetal.2014, author = {Vergho, Daniel Claudius and Kneitz, Susanne and Kalogirou, Charis and Burger, Maximilian and Krebs, Markus and Rosenwald, Andreas and Spahn, Martin and L{\"o}ser, Andreas and Kocot, Arkadius and Riedmiller, Hubertus and Kneitz, Burkhard}, title = {Impact of miR-21, miR-126 and miR-221 as Prognostic Factors of Clear Cell Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava}, doi = {10.1371/journal.pone.0109877}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113633}, year = {2014}, abstract = {Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.}, language = {en} } @article{MortonFliesserDittrichetal.2014, author = {Morton, Charles Oliver and Fliesser, Mirjam and Dittrich, Marcus and M{\"u}ller, Tobias and Bauer, Ruth and Kneitz, Susanne and Hope, William and Rogers, Thomas Richard and Einsele, Hermann and L{\"o}ffler, J{\"u}rgen}, title = {Gene Expression Profiles of Human Dendritic Cells Interacting with Aspergillus fumigatus in a Bilayer Model of the Alveolar Epithelium/Endothelium Interface}, doi = {10.1371/journal.pone.0098279}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112893}, year = {2014}, abstract = {The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA.}, language = {en} } @article{KneitzKalogirouSpahnetal.2013, author = {Kneitz, Burkhard and Kalogirou, Charis and Spahn, Martin and Krebs, Markus and Joniau, Steven and Lerut, Evelyne and Burger, Maximilian and Scholz, Claus-J{\"u}rgen and Kneitz, Susanne and Riedmiller, Hubertus}, title = {MiR-205 Is Progressively Down-Regulated in Lymph Node Metastasis but Fails as a Prognostic Biomarker in High-Risk Prostate Cancer}, series = {International Journal of Molecular Sciences}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms141121414}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97321}, year = {2013}, abstract = {The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70\% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa.}, language = {en} } @article{SchubertSpahnKneitzetal.2013, author = {Schubert, Maria and Spahn, Martin and Kneitz, Susanne and Scholz, Claus J{\"u}rgen and Joniau, Steven and Stroebel, Philipp and Riedmiller, Hubertus and Kneitz, Burkhard}, title = {Distinct microRNA Expression Profile in Prostate Cancer Patients with Early Clinical Failure and the Impact of let-7 as Prognostic Marker in High-Risk Prostate Cancer}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0065064}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96825}, year = {2013}, abstract = {Background The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. Methodology and Principal Findings We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. Conclusion Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.}, language = {en} } @article{DeekenGohlkeScholzetal.2013, author = {Deeken, Rosalia and Gohlke, Jochen and Scholz, Claus-Juergen and Kneitz, Susanne and Weber, Dana and Fuchs, Joerg and Hedrich, Rainer}, title = {DNA Methylation Mediated Control of Gene Expression Is Critical for Development of Crown Gall Tumors}, series = {PLoS Genetics}, journal = {PLoS Genetics}, doi = {10.1371/journal.pgen.1003267}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96318}, year = {2013}, abstract = {Crown gall tumors develop after integration of the T-DNA of virulent Agrobacterium tumefaciens strains into the plant genome. Expression of the T-DNA-encoded oncogenes triggers proliferation and differentiation of transformed plant cells. Crown gall development is known to be accompanied by global changes in transcription, metabolite levels, and physiological processes. High levels of abscisic acid (ABA) in crown galls regulate expression of drought stress responsive genes and mediate drought stress acclimation, which is essential for wild-type-like tumor growth. An impact of epigenetic processes such as DNA methylation on crown gall development has been suggested; however, it has not yet been investigated comprehensively. In this study, the methylation pattern of Arabidopsis thaliana crown galls was analyzed on a genome-wide scale as well as at the single gene level. Bisulfite sequencing analysis revealed that the oncogenes Ipt, IaaH, and IaaM were unmethylated in crown galls. Nevertheless, the oncogenes were susceptible to siRNA-mediated methylation, which inhibited their expression and subsequently crown gall growth. Genome arrays, hybridized with methylated DNA obtained by immunoprecipitation, revealed a globally hypermethylated crown gall genome, while promoters were rather hypomethylated. Mutants with reduced non-CG methylation developed larger tumors than the wild-type controls, indicating that hypermethylation inhibits plant tumor growth. The differential methylation pattern of crown galls and the stem tissue from which they originate correlated with transcriptional changes. Genes known to be transcriptionally inhibited by ABA and methylated in crown galls became promoter methylated upon treatment of A. thaliana with ABA. This suggests that the high ABA levels in crown galls may mediate DNA methylation and regulate expression of genes involved in drought stress protection. In summary, our studies provide evidence that epigenetic processes regulate gene expression, physiological processes, and the development of crown gall tumors.}, language = {en} } @article{VerghoKneitzRosenwaldetal.2014, author = {Vergho, Daniel and Kneitz, Susanne and Rosenwald, Andreas and Scherer, Charlotte and Spahn, Martin and Burger, Maximilian and Riedmiller, Hubertus and Kneitz, Burkhard}, title = {Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma}, doi = {10.1186/1471-2407-14-25}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110061}, year = {2014}, abstract = {Background Renal cell carcinoma (RCC) is marked by high mortality rate. To date, no robust risk stratification by clinical or molecular prognosticators of cancer-specific survival (CSS) has been established for early stages. Transcriptional profiling of small non-coding RNA gene products (miRNAs) seems promising for prognostic stratification. The expression of miR-21 and miR-126 was analysed in a large cohort of RCC patients; a combined risk score (CRS)-model was constructed based on expression levels of both miRNAs. Methods Expression of miR-21 and miR-126 was evaluated by qRT-PCR in tumour and adjacent non-neoplastic tissue in n = 139 clear cell RCC patients. Relation of miR-21 and miR-126 expression with various clinical parameters was assessed. Parameters were analysed by uni- and multivariate COX regression. A factor derived from the z-score resulting from the COX model was determined for both miRs separately and a combined risk score (CRS) was calculated multiplying the relative expression of miR-21 and miR-126 by this factor. The best fitting COX model was selected by relative goodness-of-fit with the Akaike information criterion (AIC). Results RCC with and without miR-21 up- and miR-126 downregulation differed significantly in synchronous metastatic status and CSS. Upregulation of miR-21 and downregulation of miR-126 were independently prognostic. A combined risk score (CRS) based on the expression of both miRs showed high sensitivity and specificity in predicting CSS and prediction was independent from any other clinico-pathological parameter. Association of CRS with CSS was successfully validated in a testing cohort containing patients with high and low risk for progressive disease. Conclusions A combined expression level of miR-21 and miR-126 accurately predicted CSS in two independent RCC cohorts and seems feasible for clinical application in assessing prognosis.}, language = {en} } @article{LangenhorstGogishviliRibechinietal.2012, author = {Langenhorst, Daniela and Gogishvili, Tea and Ribechini, Eliana and Kneitz, Susanne and McPherson, Kirsty and Lutz, Manfred B. and H{\"u}nig, Thomas}, title = {Sequential induction of effector function, tissue migration and cell death during polyclonal activation of mouse regulatory T-cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76009}, year = {2012}, abstract = {The ability of CD4+Foxp3+ regulatory T-cells (Treg) to produce interleukin (IL)-10 is important for the limitation of inflammation at environmental interfaces like colon or lung. Under steady state conditions, however, few Tregs produce IL-10 ex vivo. To investigate the origin and fate of IL-10 producing Tregs we used a superagonistic mouse anti-mouse CD28 mAb (CD28SA) for polyclonal in vivo stimulation of Tregs, which not only led to their numeric expansion but also to a dramatic increase in IL-10 production. IL-10 secreting Tregs strongly upregulated surface receptors associated with suppressive function as compared to non-producing Tregs. Furthermore, polyclonally expanding Tregs shifted their migration receptor pattern after activation from a CCR7+CCR52 lymph node-seeking to a CCR72CCR5+ inflammationseeking phenotype, explaining the preferential recruitment of IL-10 producers to sites of ongoing immune responses. Finally, we observed that IL-10 producing Tregs from CD28SA stimulated mice were more apoptosis-prone in vitro than their IL-10 negative counterparts. These findings support a model where prolonged activation of Tregs results in terminal differentiation towards an IL-10 producing effector phenotype associated with a limited lifespan, implicating built-in termination of immunosuppression.}, subject = {Medizin}, language = {en} } @article{SchartlKneitzWildeetal.2012, author = {Schartl, Manfred and Kneitz, Susanne and Wilde, Brigitta and Wagner, Toni and Henkel, Christiaan V. and Spaink, Hermann P. and Meierjohann, Svenja}, title = {Conserved expression signatures between medaka and human pigment cell tumors}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75848}, year = {2012}, abstract = {Aberrations in gene expression are a hallmark of cancer cells. Differential tumor-specific transcript levels of single genes or whole sets of genes may be critical for the neoplastic phenotype and important for therapeutic considerations or useful as biomarkers. As an approach to filter out such relevant expression differences from the plethora of changes noted in global expression profiling studies, we searched for changes of gene expression levels that are conserved. Transcriptomes from massive parallel sequencing of different types of melanoma from medaka were generated and compared to microarray datasets from zebrafish and human melanoma. This revealed molecular conservation at various levels between fish models and human tumors providing a useful strategy for identifying expression signatures strongly associated with disease phenotypes and uncovering new melanoma molecules.}, subject = {Biologie}, language = {en} } @article{RiedelMofoloAvotaetal.2013, author = {Riedel, Alice and Mofolo, Boitumelo and Avota, Elita and Schneider-Schaulies, Sibylle and Meintjes, Ayton and Mulder, Nicola and Kneitz, Susanne}, title = {Accumulation of Splice Variants and Transcripts in Response to PI3K Inhibition in T Cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-77917}, year = {2013}, abstract = {Background: Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Hypothesis: Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. Methods: To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. Results: Applying our algorithm to the data, 9\% of the genes were assigned as AS, while only 3\% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. Conclusions: PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.}, subject = {Biologie}, 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} } @article{KangManousakiFranchinietal.2015, author = {Kang, Ji Hyoun and Manousaki, Tereza and Franchini, Paolo and Kneitz, Susanne and Schartl, Manfred and Meyer, Axel}, title = {Transcriptomics of two evolutionary novelties: how to make a sperm-transfer organ out of an anal fin and a sexually selected "sword" out of a caudal fin}, series = {Ecology and Evolution}, volume = {5}, journal = {Ecology and Evolution}, number = {4}, doi = {10.1002/ece3.1390}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144139}, pages = {848-864}, year = {2015}, abstract = {Swords are exaggerated male ornaments of swordtail fishes that have been of great interest to evolutionary biologists ever since Darwin described them in the Descent of Man (1871). They are a novel sexually selected trait derived from modified ventral caudal fin rays and are only found in the genus Xiphophorus. Another phylogenetically more widespread and older male trait is the gonopodium, an intromittent organ found in all poeciliid fishes, that is derived from a modified anal fin. Despite many evolutionary and behavioral studies on both traits, little is known so far about the molecular mechanisms underlying their development. By investigating transcriptomic changes (utilizing a RNA-Seq approach) in response to testosterone treatment in the swordtail fish, Xiphophorus hellerii, we aimed to better understand the architecture of the gene regulatory networks underpinning the development of these two evolutionary novelties. Large numbers of genes with tissue-specific expression patterns were identified. Among the sword genes those involved in embryonic organ development, sexual character development and coloration were highly expressed, while in the gonopodium rather more morphogenesis-related genes were found. Interestingly, many genes and genetic pathways are shared between both developing novel traits derived from median fins: the sword and the gonopodium. Our analyses show that a larger set of gene networks was co-opted during the development and evolution of the older gonopodium than in the younger, and morphologically less complex trait, the sword. We provide a catalog of candidate genes for future efforts to dissect the development of those sexually selected exaggerated male traits in swordtails.}, language = {en} } @article{SimonRauskolbGunnersenetal.2015, author = {Simon, Christian M. and Rauskolb, Stefanie and Gunnersen, Jennifer M. and Holtmann, Bettina and Drepper, Carsten and Dombert, Benjamin and Braga, Massimiliano and Wiese, Stefan and Jablonka, Sibylle and P{\"u}hringer, Dirk and Zielasek, J{\"u}rgen and Hoeflich, Andreas and Silani, Vincenzo and Wolf, Eckhard and Kneitz, Susanne and Sommer, Claudia and Toyka, Klaus V. and Sendtner, Michael}, title = {Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy}, series = {Acta Neuropathologica}, volume = {130}, journal = {Acta Neuropathologica}, doi = {10.1007/s00401-015-1446-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154569}, pages = {373 -- 387}, year = {2015}, abstract = {Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.}, language = {en} } @article{JessenKressBaluapurietal.2020, author = {Jessen, Christina and Kreß, Julia K. C. and Baluapuri, Apoorva and Hufnagel, Anita and Schmitz, Werner and Kneitz, Susanne and Roth, Sabine and Marquardt, Andr{\´e} and Appenzeller, Silke and Ade, Casten P. and Glutsch, Valerie and Wobser, Marion and Friedmann-Angeli, Jos{\´e} Pedro and Mosteo, Laura and Goding, Colin R. and Schilling, Bastian and Geissinger, Eva and Wolf, Elmar and Meierjohann, Svenja}, title = {The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression}, series = {Oncogene}, volume = {39}, journal = {Oncogene}, issn = {0950-9232}, doi = {10.1038/s41388-020-01477-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235064}, pages = {6841-6855}, year = {2020}, abstract = {The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H\(_2\)O\(_2\) or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.}, language = {en} } @article{KrebsBehrmannKalogirouetal.2019, author = {Krebs, Markus and Behrmann, Christoph and Kalogirou, Charis and Sokolakis, Ioannis and Kneitz, Susanne and Kruithof-de Julio, Marianna and Zoni, Eugenio and Rech, Anne and Schilling, Bastian and K{\"u}bler, Hubert and Spahn, Martin and Kneitz, Burkhard}, title = {miR-221 Augments TRAIL-mediated apoptosis in prostate cancer cells by inducing endogenous TRAIL expression and targeting the functional repressors SOCS3 and PIK3R1}, series = {BioMed Research International}, volume = {2019}, journal = {BioMed Research International}, doi = {10.1155/2019/6392748}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202480}, pages = {6392748}, year = {2019}, abstract = {miR-221 is regarded as an oncogene in many malignancies, and miR-221-mediated resistance towards TRAIL was one of the first oncogenic roles shown for this small noncoding RNA. In contrast, miR-221 is downregulated in prostate cancer (PCa), thereby implying a tumour suppressive function. By using proliferation and apoptosis assays, we show a novel feature of miR-221 in PCa cells: instead of inducing TRAIL resistance, miR-221 sensitized cells towards TRAIL-induced proliferation inhibition and apoptosis induction. Partially responsible for this effect was the interferon-mediated gene signature, which among other things contained an endogenous overexpression of the TRAIL encoding gene TNFSF10. This TRAIL-friendly environment was provoked by downregulation of the established miR-221 target gene SOCS3. Moreover, we introduced PIK3R1 as a target gene of miR-221 in PCa cells. Proliferation assays showed that siRNA-mediated downregulation of SOCS3 and PIK3R1 mimicked the effect of miR-221 on TRAIL sensitivity. Finally, Western blotting experiments confirmed lower amounts of phospho-Akt after siRNA-mediated downregulation of PIK3R1 in PC3 cells. Our results further support the tumour suppressing role of miR-221 in PCa, since it sensitises PCa cells towards TRAIL by regulating the expression of the oncogenes SOCS3 and PIK3R1. Given the TRAIL-inhibiting effect of miR-221 in various cancer entities, our results suggest that the influence of miR-221 on TRAIL-mediated apoptosis is highly context- and entity-dependent.}, language = {en} } @article{HelmprobstKneitzKlotzetal.2021, author = {Helmprobst, Frederik and Kneitz, Susanne and Klotz, Barbara and Naville, Magali and Dechaud, Corentin and Volff, Jean-Nicolas and Schartl, Manfred}, title = {Differential expression of transposable elements in the medaka melanoma model}, series = {PLoS One}, volume = {16}, journal = {PLoS One}, number = {10}, doi = {10.1371/journal.pone.0251713}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260615}, year = {2021}, abstract = {Malignant melanoma incidence is rising worldwide. Its treatment in an advanced state is difficult, and the prognosis of this severe disease is still very poor. One major source of these difficulties is the high rate of metastasis and increased genomic instability leading to a high mutation rate and the development of resistance against therapeutic approaches. Here we investigate as one source of genomic instability the contribution of activation of transposable elements (TEs) within the tumor. We used the well-established medaka melanoma model and RNA-sequencing to investigate the differential expression of TEs in wildtype and transgenic fish carrying melanoma. We constructed a medaka-specific TE sequence library and identified TE sequences that were specifically upregulated in tumors. Validation by qRT- PCR confirmed a specific upregulation of a LINE and an LTR element in malignant melanomas of transgenic fish.}, language = {en} } @article{SchartlKneitzVolkoffetal.2019, author = {Schartl, Manfred and Kneitz, Susanne and Volkoff, Helene and Adolfi, Mateus and Schmidt, Cornelia and Fischer, Petra and Minx, Patrick and Tomlinson, Chad and Meyer, Axel and Warren, Wesley C.}, title = {The piranha genome provides molecular insight associated to its unique feeding behavior}, series = {Genome Biology and Evolution}, volume = {11}, journal = {Genome Biology and Evolution}, number = {8}, doi = {10.1093/gbe/evz139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202218}, pages = {2099-2106}, year = {2019}, abstract = {The piranha enjoys notoriety due to its infamous predatory behavior but much is still not understood about its evolutionary origins and the underlying molecular mechanisms for its unusual feeding biology. We sequenced and assembled the red-bellied piranha (Pygocentrus nattereri) genome to aid future phenotypic and genetic investigations. The assembled draft genome is similar to other related fishes in repeat composition and gene count. Our evaluation of genes under positive selection suggests candidates for adaptations of piranhas' feeding behavior in neural functions, behavior, and regulation of energy metabolism. In the fasted brain, we find genes differentially expressed that are involved in lipid metabolism and appetite regulation as well as genes that may control the aggression/boldness behavior of hungry piranhas. Our first analysis of the piranha genome offers new insight and resources for the study of piranha biology and for feeding motivation and starvation in other organisms.}, language = {en} }