Bullerdiek, Jörn
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Bullerdiek, Jörn
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Bullerdiek, Jörn
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Bullerdiek, Joern
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Item-typ:Veröffentlichung, Untersuchungen zur Funktion der HMGA- und HMGB-Subfamilien bei der Tumorentstehung.(2003-09-19); ; ; Proteins encoded by the genes HMGA1, HMGA2 und HMGB1 are architectural transcription factors whose interaction with DNA lead to a conformational change affecting the assembly of functional multiprotein-complexes.Different benign mesenchymal tumor entities are characterized by chromosomal aberrations within 12q14-15 or 6p21.3 show rearrangements of HMGA2 or HMGA1, respectively.Chromosomal breakpoints affecting HMGA1 were predominantly located within the 3 flanking region leading to the expression of aberrant transcripts. Expression of HMGA1 and HMGA2 is under control of functional elements located within their 3 UTR.Truncation of these elements as found within tumors is associated with an increased expression.The HMGA2 5 flanking region contains two functionally independent promoter and a (TC)-repeat whose repeat length is crucial for expressional activity. A high affinity HMGA2 binding site was mapped within the ERCC1 promoter. Comparison of binding to this region between HMGA2 and Cterminally truncated ΔHMGA2 showed that the acidic C-tail had no influence on binding affinity but is associated with differences in pattern, stoichiometry, and mechanisms of DNA-binding. These differences led to a significant change in DNA-conformation and a stronger inhibition of ERCC1 promoter activity due to ΔHMGA2. Expression array analyses of myometrial cells induced by native and aberrant HMGA proteins showed that besides their structural differences the HMGA variants are functionally related to each other. Genes functionally involved in proliferation and differentiation were predominantly down-regulated by HMGA in normal myometrial cells. A new gene (LBH) was mapped in tail-to-tail orientation directly behind HMGA1. Its expression was not significantly altered in tumors with 6p21.3 aberration. Genomic sequence of human HMGB1 was completed and its promoter was functionally characterized. An intertumoral variation of HMGB1 expression was found in breast cancDissertation251 138 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Gene expression differences in cardiovascular disease(2015-01-12); ; ; The results of three studies about gene expression differences in cardiovascular disease are presented within this thesis. The first topic covers the involvement of the HMGA2 gene in cellular processes found in acute aortic dissection, a disease characterised by the splitting of the aortic layers leading to a high mortality. The results suggest the upregulation of HMGA2 in the endothelium of aortic dissection tissue, accompanied by the transition of these endothelial cells to mesenchymal cells. The second study focuses on differences of the spatial distribution of the eNOS protein within the aorta of patients with bicuspid aortic valve, a common congenital heart defect. The results of this study indicate the spatial dyregulation of the eNOS protein, probably due to an altered hemodynamic, and the associated irregular nitric oxide distribution. The miRNA 208a was quantified in tissue of atrial fibrillation patients in the third study. The miRNA expression was significantly decreased in long-standing persistent atrial fibrillation compared to persistent atrial fibrillation, suggesting a decline over the course of the arrhythmia.Dissertation293 143 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Untersuchungen zur Genetik von Speicheldrüsentumoren(2009-11-26); ; ; We have analyze the recently for mucoepidermoid carcinoma (MEC) and Warthin's tumor (WAT) described gene fusion CRTC1-MAML2 for its diagnostic potential as biomarker and to find out if an aberrant HMGA2 expression level influence tumorgenesis of MECs. Our studies have shown that a CRTC1-MAML2 test is a powerful tool for diagnosis and prognosis of MECs. The fusion correlates with a low- or intermediate-grade of the tumor and is associated with a favorable prognosis. CRTC1-MAML2 negative tumors were mainly found in high-grade tumors and show a significant increased HMGA2 level. These data raise doubts about the correct classification of MECs into low-, intermediate- and high-grade tumors. In our opinion the present classification of MECs includes two subgroups: A huge group of "true-MECs" with the CRTC1-MAML2 fusion, with a moderate aggressiveness and furthermore a group of morphological heterogeneous tumors lacking this fusion and with an aberrantly high HMGA2 expression level.Dissertation258 95 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Dysregulation of the high mobility group AT-hook 2 (HMGA2) gene in human tumours(2014-07-11); ; ; The high mobility group AT-hook 2 (HMGA2) gene is expressed during embryogenesis but silenced in adult tissues. It often is reactivated for varying reasons depending on tissue type in a variety of malignant and benign tumours contributing to tumour growth. In this thesis, causes for dysregulation in various human tissues were investigated. A potential HMGA2 increase upon growth factor incubation was investigated in the epithelial prostate cancer cell line PC-3 as well as in human umbilical vein endothelial cells. The underlying mechanism for HMGA2 silencing in the prostate cancer cell line LNCaP was examined as well as effects of HMGA2 on cell viability. Furthermore, a small subset of uterine leiomyomas was tested by high-resolution array-based comparative genomic hybridisation to detect microdeletions potentially related to the breakpoints accompanying the typical translocation responsible for HMGA2 reactivation. An HMGA2 increase in PC-3 cells upon growth factor and FBS incubation was not detected, whereat it was shown in HUVECs upon growth factor incubation. HMGA2 in non-expressing LNCaP cells was found to be detectable after incubation with a demethylating agent, but not after silencing of DICER1, pointing rather to the involvement of DNA methylation than of miRNAs in HMGA2 silencing. Furthermore, HMGA2 incubation was associated with reduced cell viability. In two of the three uterine leiomyomas, small deletions that may be associated with the translocation were identified upstream of the HMGA2 locus. The results obtained herein underline the versatility of HMGA2 in regulation and function supporting the need for individual consideration for the development of potential therapeutic applications.Dissertation294 159 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Untersuchungen zur Bedeutung ausgewählter HMG-Proteine bei der Differenzierung und Prolieferation von Endothel- und glatten Muskelzellen(2005-03-04); ; ; Arteriosklerose ist ein Oberbegriff für vaskuläre Erkrankungen. Durch parakrine Freisetzung von Wachstumsfaktoren und Zytokinen migrieren proliferative glatte Muskelzellen aus der Media in die Intima unter Bildung einer Neointima. Neben der Proliferation und Migration von glatten Muskelzellen spielt die pathologische Angiogenese im Rahmen der Arteriosklerose eine entscheidende Rolle.Im Rahmen dieser Dissertation wurde die funktionelle Bedeutung ausgewählter High Mobility Group (HMG)-Proteine auf humane vaskuläre Zellen bei der Pathogenese arteriosklerotischer Läsionen untersucht. Durch immunhistochemische Untersuchungen und RT-PCR-Analysen konnte erstmalig das HMGA1-, HMGA2- und HMGB1-Expressionsmuster in humanen arteriosklerotischen Plaques beschrieben werden. RT-PCR-Analysen der HMGA1- und HMGB1-Expression ergaben eine ubiquitäre Expression. Das HMGA2-Expressionsmuster war dahingegen heterogen. Weiterführende Untersuchungen zeigten, daß die exogene Applikation von rekombinantem HMGA1- und HMGA2-Proteinen einen signifikanten proliferativen Effekt auf humane glatte Muskelzellen induzierte. Desweiteren konnte im Rahmen dieser Arbeit erstmalig gezeigt werden, daß den HMGA1-, HMGA2 und HMGB1-Proteinen eine essentielle Rolle bei der Entstehung von kleinen Blutgefäßen in arteriosklerotischen Plaques zukommt. Es konnten in allen humanen arteriosklerotischen Plaques neugebildete Blutgefäße detektiert werden. Desweiteren führte die exogene Applikation von rekombinanten HMGA1- und HMGB1-Proteinen in einem dreidimensionalen Sphäroidmodell von humanen Endothelzellen (HUVECs) zur signifikanten, dosisabhängigen kapillarähnlichen Endothelaussprossung. In seiner Funktion als extrazelluläres Protein kann HMGB1 über den Transmembranrezeptor RAGE agieren. Es konnten im Rahmen dieser Dissertation erstmalig drei neue mRNA Varianten des Rezeptors identifiziert und charakterisiert werden, die verkürzte, lösliche Rezeptorvarianten kodieren und als kompetitive Inhibitoren der RAGE-vermiDissertation221 150 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Vergleichende Tumorgenetik: Der Hund (Canis familiaris) als Modelltier für die humane Tumorgenese(2007-07-17); ; ; Animal models have been used in cancer research for a long time. Due to the similari-ties of human and canine cancer the dog has gained importance as the animal of choice for therapeutic and preclinical studies. Dogs and humans are exposed to comparable life- and environmental conditions. Tumours in dogs occur spontaneously and show similar biological behaviour and pathohistological findings. However, by using the the dog as an animal model it is easier to observe large quantities of tumours in less time, because of the faster progression of the tumours and the larger numbers of descendants compared to their human counterparts. Even cancer progression as well as effectiveness of the therapy of choice can be more easily observed.This thesis is addressed to different aspects of canine tumour development and is divided into five sections: Cytogenetic investigations in canine neoplasias, physical mapping of different tumour-associated genes in the canine genome, establishment of a tissue bank, HMGA2 expression in different canine prostatic tissues and cell culture, as well as the development of new therapeutic approaches using adeno-associated viruses.Cytogenetic investigation of canine neoplasias showed clonal aberrations like trisomies or centric fusions of canine chromosomes. The latter is rarely seen in man, while it is a frequent event in canine tumourigenesis. The frequent appearance of ab-errations (numeric as well as structural) affecting the canine chromosome 13 is of no-table interest, as CFA13, which shares homology with human chromosome 8, seems to contain important genes associated with the development of cancer. Knowledge about localisation and structure of several tumour-associated genes is precondition for better understanding of the function of these genes. This again is ba-sic requirement for the development of new therapeutic approaches. Herein a subset of six selected tumour associated genes have been physically mapped by fluores-cence in situ hybridization. By using tissue samples of the newly established tissue bank for tumours and non neoplastic tissues, some of these genes were further inves-tigated with respect to cDNA-structure, partial DNA-structure and protein-expression.Special attention was called on HMGA2 Expression in canine prostatic tissues. To elucidate the question if HMGA2 proteins are overexpressed in canine prostate carci-nomas, four non-neoplastic tissues of the canine prostate, three prostatic cysts, three canine prostatic hyperplasias and six canine carcinomas of the prostate as well as cells of the newly established prostate carcinoma cell-line were examined by quantita-tive real time PCR in respect to HMGA2 expression. Those investigations clearly showed a correlation between pathohistological findings and HMGA2 expression. Furthermore, adeno-associated viruses were generated, carrying HMGA1 and HMGA2 in antisense orientation. The infection of cells of the spontaneously immortal-ized cell-line CT1258 with those viruses lead to a statistically significant reduction of cell growth and viabilitiy, whereas the infection of cells with viruses carrying LacZ or no insert at all did not show any statistically significant reduction of cell growth. This antisense strategy for suppression of HMGA2 expression seems to be an effective target for the treatment of both, canine and human prostate carcinoma as well as any other tumour showing overexpression of HMGA2. Due to the fact of the very low or even absent expression of HMGA2 in adult organisms, very little side effects are to be expected.Dissertation257 177 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Untersuchungen zur Expression ausgewählter Stammzellgene an embryonalen Geweben und Tumoren(2017-05-30); ; ; HMGA2 and miRNAs of C19MC and miR-371-3 are mainly expressed in embryonic tissues. Reexpression of these genes can be found in different types of tumours. The influence of the above mentioned genes on development and growth was investigated in placentas and testicular germ cell tumours, which mimic embryonic development. Invasive growth is a characteristic of placentas and tumours. Therefore, analysis of the underlying regulation processes in placental development might help to understand the induction of invasive behavior in tumours. In this thesis, investigation of spontaneous and induced abortions and of full-term placentas revealed increasing expression of miRNAs of C19MC with the progression of pregnancy. According to literature, this seems to be related to the regulation of invasive growth of trophoblast cells. Particularly the expression level of miRNAs of the miR-371-3 cluster showed strong interindividual differences. This was not caused by the site of the placenta where the sample has been taken from. Additionally, interindividual differences in expression of miR-371a-3p were also observed in serum samples. It remains to be elucidated whether or not they affect processes during prenatal life. Since there were no differences in expression of spontaneous compared to induced abortions, the miRNAs examined do not play an obvious role in miscarriage events. Investigations conducted in this thesis revealed high HMGA2 expression in first trimester placentas followed by a decline to a baseline level which can be observed until birth. High HMGA2 expression correlated with the low oxygen environment in the uterus in early pregnancy which is known to be a requirement for the proliferation of trophoblast cells. Hence, HMGA2 might function as a proliferation factor in this context. No difference in expression of spontaneous compared to induced abortions could be detected. This indicates that HMGA2 has no obvious role in spontaneous abortions. The stem cell factor HMGA2 was mainly detected in stromal cells of placental villi. This is in concordance with the previous finding that stem cell are located in the stroma of placental villi. Another interesting result of this thesis was the finding that in trophoblast cells HMGA2 is located mostly in the cytoplasma. Cytoplasmatic expression might be related to extravillous differentiation of cytotrophoblast as shown for HMGA1. While physiological expression of HMGA2 is mainly restricted to embryonic tissues and stem cells, reexpression can be observed in different types of tumours. Due to the fact that testicular germ cell tumours mimic embryonic tissues, HMGA2 expression was measured in different types of postpubertal testicular germ cell tumours. Tumours comprising of only one subgroup could be distinguished by qRT PCR expression levels. In frequently found mixed tumours, classification via HMGA2 expression is less distinct. By using HMGA2 immunohistochemistry subgroups could be distinguished. To establish HMGA2 in clinical application, the investigation should be extended on a larger sample. HMGA2 staining showed promising results in detecting choriocarcinoma components. Convincing evidence was found for HMGA2 as an appropriate marker for the detection of yolk sac components.Dissertation342 111 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Molekularzytogenetische und molekulargenetische Untersuchungen an Schilddrüsentumoren(2012-05-23); ; ; The focus of the present study was on the molecular-cytogenetic analysis of the main cytogenetic subgroups in follicular lesions of the thyroid. Quantitative molecular-cytogenetic analysis of benign thyroid lesions revealed that much greater importance is attached to the main cytogenetic subgroups, i.e. trisomy 7 and rearrangements of 2p21 or 19q13.4, than by conventional cytogenetic analysis alone. For 2p21-rearrangements it was possible to identify and to further characterize the target gene, THADA, involved in these rearrangements. Further analyses suggest that the truncation of THADA is in correlation with the proliferation of epithelial cells und the genesis of benign thyroid lesions. For 19q13.4 rearrangements the breakpoints were narrowed down to a region of about 150 kb which is in close proximity to two miRNA clusters, C19MC and mir-371-3, which both are activated as a result of the rearrangements. The molecular-cytogenetic analysis of benign as well as malign follicular thyroid neoplasias with respect to the translocation t(2;3)(q13;p25) and the PAX8/PPARγ fusion gene, respectively, revealed that this aberration occurs only in a small fraction of follicular adenomas. Molecular-cytogenetic characterization of the 3p25 breakpoint region reveals that rearrangements of the 3p25 region occur independently of the 2q13 region and the PAX8 gene, respectively. Thus this region is considered as a hot spot region in thyroid neoplasias with follicular origin. In conclusion the results of the present study point out the status of molecular cytogenetics with respect to the analysis of tumor-specific chromosomal aberrations in general and in particular to the relevance of these aberrations to the pathogenesis of benign follicular thyroid lesions.Dissertation305 287 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, UNTERSUCHUNGEN ZUR MOLEKULAREN PATHOGENESE VON FOLLIKULÄREN SCHILDDRÜSENTUMOREN(2003-11-25); ; ; Thyroid tumors belong to the most frequent epithelial tumors. On the basis of their histologically and clinically definable forms and stages they represent an outstanding model system for tumorgenesis. Cytogenetic analyses can serve here as an excellent and efficient tool for cloning tumor-relevant genes. Known important cytogenetic changes in adenomas are trisomy 7 as well as breaks in chromosomal bands 19q13.4 and 2p21. Starting from these data, in the present work the breakpoint cluster 19q13.4 was cloned. The newly found upstream lying zinc finger gene ZNF331 was described as a candidate-gene. The second relevant breakpoint cluster in band 2p21 was cloned as well. Here the newly found candidate gene THADA was described which fuses through translocations to different other chromosomes, creating a truncated fusion protein. It could clearly be shown that the HMGA2 gene has an influence on the tumor progression of epithelial thyroid gland cells. Since in animal tissues HMGA2, as shown in mice, is only active during the embryonal stages, the issue arises whether an observed overexpression evokes a tumorigenic status and therefore might be a suitable central point of application for a therapy.Dissertation219 102 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Molekulargenetische Untersuchungen zum Spleißen ausgewählter High Mobility Group Protein-Gene.(2004-05-18); ; ; Chromosomal rearrangements of the HMGA2 locus belong to the most common aberrations in human benign tumors. HMGA2 rearrangements often result in chimeric genes expressing transcripts consisting of the first three exons of HMGA2 followed by ectopic sequences which have been assigned to chromosome 12 by CASH analysis. These ectopic sequences can be assumed either to result from aberrant splicing with the sequences derived from Intron 3 or 4 of HMGA2 or to represent true ectopic sequences derived from other genes on chromosome 12.To address that question, the entire introns 3 and 4 of HMGA2 have been cloned, sequenced and characterized. It was shown that 5 ectopic sequences formerly described as fused to HMGA2 exon 3 are localized within the third intron of that gene. 3 ectopic sequences formerly described as fused to HMGA2 exon 4 have been localized within the third intron of that gene. RT-PCR based expression studies revealed a co-expression of these transcripts in tumor samples as well as in normal tissues. As these additional HMGA2 transcripts can be detected in cells with a normal karyotype verified by FISH analysis it is quite obviously that these transcripts are alternative not aberrant splice-products of the HMGA2 gene.In silico analysis of the alternative terminal exons of HMGA2 and surrounding intronic sequences revealed a high homology to well established consensus sequences for the 5 splice donor site, 3 splice acceptor site, and the branch site. Potential polyadenylation signals were detected as well. Northern blot hybridizations of the lipoma cell line Li-14 revealed the expression of five additional HMGA2 transcripts consisting of exons 1 to 3 but not exons 4 to 5 besides the wild-type full-length HMGA2 transcript.Therefore, a model for the HMGA2-dependent tumorigenesis was postulated in which the expression of HMGA2 and its splice-variants is integrated in a complex network of mutual dependences.Dissertation255 349