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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Étude génomique et fonctionnelle de la dérégulation du gène HMGA2 dans les tumeurs adipocytaires / Genomic and functional study of HMGA2 deregulation in adipocytic tumors

Saada-Bouzid, Esma 05 February 2015 (has links)
Les tumeurs adipocytaires (TA) bénignes sont majoritairement constituées par les lipomes, alors que les TA malignes sont principalement des Tumeurs Lipomateuses Atypiques (TLA)/ liposarcome (LPS) bien différenciés (LBD) et les LPS dédifférenciés (LDD). Le gène HMGA2 (High Mobility Group A2) est remanié dans certains lipomes et amplifié dans les TLA/LBD et LDD. Ainsi, nous avons émis l’hypothèse que HMGA2 jouait un rôle fondamental dans la genèse des TA bénignes et malignes. En faveur de cette hypothèse, nous avons observé une surexpression constante de HMGA2 dans les TLA/LBD et LDD avec amplification de HMGA2 et les lipomes avec remaniement de HMGA2. Dans un cas de lipomatose, hypertrophie pathologique du tissu adipeux sans anomalie du gène HMGA2, une surexpression de HMGA2 était associée à une inhibition de l’expression de plusieurs microARN let-7. En revanche, nos travaux ne sont pas en faveur d’un rôle prépondérant des microARN let7 dans la surexpression de HMGA2 dans les TA. Nous nous sommes également intéressés aux gènes partenaires de fusion avec HMGA2 dans les lipomes et avons notamment identifié une nouvelle fusion impliquant PPAP2B (Phosphatidic Acid Phosphatase type 2B) localisé en 1p32. Nous avons aussi confirmé le rôle du gène NFIB (9p22) dans les lipomes. Enfin, nous avons établi des corrélations pronostiques dans une grande série de 116 TLA/LBD et LDD : l’amplification de HMGA2 était associée à l’histotype TLA/LBD et à une survie longue alors que les amplifications de CDK4 et JUN sont associées au type LDD et une survie courte. Ainsi, nos données confortent l’hypothèse d’un rôle précoce et majeur de HMGA2 dans la genèse des TA bien différenciées. / Benign adipocytic tumors (AT) are mainly represented by lipomas whereas most malignant AT are Atypical Lipomatous Tumors/Well-differentiated liposarcomas (ALT/WDLPS) and dedifferentiated liposarcomas (DDLPS). HMGA2 gene (High Mobility Group A2) is rearranged in some lipomas and amplified in ALT/WDLPS and DDLPS. Thus, we hypothesized that HMGA2 played a fundamental role in benign and malignant AT genesis. In favor of this hypothesis, we observed a constant overexpression of HMGA2 in amplified ALT/WDLPS and DDLPS, and in rearranged lipomas. In a case of lipomatosis, that is a pathological proliferation of the adipocytic tissu without rearrrangement of HMGA2, the overexpression of HMGA2 was asssociated with an inhibition of the expression of several let-7 microRNAs. However, we did not find a leading role of let-7 microRNAs in the deregulation of HMGA2 expression in AT. We also studied partner fusion genes of HMGA2 in lipomas and have specifically identified a new fusion involving PPAP2B (Phosphatidic Acid Phosphatase type 2B) which is located in 1p32. We also confirmed the role of NFIB gene (9p22) in lipomas. Finally, we have established prognostic correlations in a series of 116 ALT/WDLPS and DDLPS: HMGA2 amplification was associated with ALT/WDLPS histotype and a longer survival whereas respective CDK4 and JUN amplification were associated with DDLPS and shorter survival. Thus, our data support the hypothesis of an early and major role of HMGA2 in the genesis well differentiated AT.
2

THE BALANCED, RECIPROCAL TRANSLOCATION OF CHROMOSOMAL SUBBANDS 12q15 AND 14q24 AND ALTERED GENE EXPRESSION IN UTERINE LEIOMYOMA

INGRAHAM, SUSAN ELIZABETH 16 September 2002 (has links)
No description available.
3

Overexpression and oncogenic function of HMGA2 in endometrial serous carcinogenesis

Wei, Linxuan, Liu, Xiaolin, Zhang, Wenjing, Wei, Yuyan, Li, Yingwei, Zhang, Qing, Dong, Ruifen, Kwon, Jungeun Sarah, Liu, Zhaojian, Zheng, Wenxin, Kong, Beihua January 2016 (has links)
The high-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor highly expressed in fetal tissue and malignant tumors but rarely detected within normal adult tissues. The clinical implications and biological functions of HMGA2 in endometrial carcinoma are largely unknown. Here we report that HMGA2 expression was barely detected in benign endometrium samples (2 of 28 samples). However, HMGA2 expression increased significantly from precancerous lesion endometrial glandular dysplasia (7 of 17, 41.2%), to serous endometrial intraepithelial carcinoma (5 of 8, 62.5%) and to full blown endometrial serous carcinoma (39 of 59, 66.1%). Functional characterization of HMGA2 revealed that the gene has both tumor growth promotion and metastasis. In addition, HMGA2 induced epithelial-mesenchymal transition (EMT) through modulation vimentin and β-catenin. Furthermore, HMGA2 overexpression started from endometrial serous precancers, non-invasive cancers, as well as in full blown carcinomas in a p53 knockout mouse model we recently established in our laboratory. Our findings suggest that HMGA2 may serve as a useful diagnostic marker in the assessment of endometrial serous cancer and its precursor lesions.
4

Transcriptional and Epigenetic Regulation of Epithelial-Mesenchymal Transition

Tan, E-Jean January 2013 (has links)
The transforming growth factor beta (TGFβ) is a cytokine that regulates a plethora of cellular processes such as cell proliferation, differentiation, migration and apoptosis. TGFβ signals via serine/threonine kinase receptors and activates the Smads to regulate gene expression. Enigmatically, TGFβ has a dichotomous role as a tumor suppressor and a tumor promoter in cancer. At early stages of tumorigenesis, TGFβ acts as a tumor suppressor by exerting growth inhibitory effects and inducing apoptosis. However, at advanced stages, TGFβ contributes to tumor malignancy by promoting invasion and metastasis. The pro-tumorigenic TGFβ potently triggers an embryonic program known as epithelial-mesenchymal transition (EMT). EMT is a dynamic process whereby polarized epithelial cells adapt a mesenchymal morphology, thereby facilitating migration and invasion. Downregulation of cell-cell adhesion molecules, such as E-cadherin and ZO-1, is an eminent feature of EMT. TGFβ induces EMT by upregulating a non-histone chromatin factor, high mobility group A2 (HMGA2). This thesis focuses on elucidating the molecular mechanisms by which HMGA2 elicits EMT. We found that HMGA2 regulates a network of EMT transcription factors (EMT-TFs), such as members of the Snail, ZEB and Twist families, during TGFβ-induced EMT. HMGA2 can interact with Smad complexes to synergistically induce Snail expression. HMGA2 also directly binds and activates the Twist promoter. We used mouse mammary epithelial cells overexpressing HMGA2, which are mesenchymal in morphology and highly invasive, as a constitutive EMT model. Snail and Twist have complementary roles in HMGA2-mesenchymal cells during EMT, and tight junctions were restored upon silencing of both Snail and Twist in these cells. Finally, we also demonstrate that HMGA2 can epigenetically silence the E-cadherin gene. In summary, HMGA2 modulates multiple reprogramming events to promote EMT and invasion.
5

Roles of high mobility group AT-hook protein 2 (HMGA2) in human cancers

Natarajan, Suchitra January 2013 (has links)
High Mobility Group AT-hook protein 2 (HMGA2) is a non-histone chromatin binding protein expressed in stem cells, cancer cells but not in normal human somatic cells. The presence of HMGA2 in cancer correlates with advanced neoplastic disease and poor prognosis. HMGA2 plays important roles in Base Excision Repair (BER) and at replication forks. HMGA2 is present at mammalian metaphase telomeres and its loss induces chromosomal aberrations. However, the functional role of HMGA2 at telomeres remains elusive. We hypothesized a protective role of HMGA2 that guards telomeres and modulates DNA damage repair signaling pathways. Employing different HMGA2+ human tumor cell models, we investigated the HMGA2-mediated functions that contribute to chemoresistance in glioblastoma (GB). This study presents a novel interaction of HMGA2 with telomeric protein TRF2 (Telomere Repeat-Binding Factor 2). This interaction retains TRF2 at telomeres, thus capping the telomeres and reducing telomere-dysfunction induced foci despite induced telomere stress. Loss of HMGA2 coincides with increased phosphorylation of TRF2, decreased TRF2 retention at telomeres and increased formation of telomeric aggregates, anaphase bridges and micronuclei. These findings provide new evidence for a unique role of HMGA2 at telomeres as a novel contributor of telomeric integrity. We show that upon DNA damage, HMGA2 causes increased and sustained phosphorylation of Ataxia Telangiectasia and Rad3-related kinase (ATR) and checkpoint kinase 1 (CHK1). Prolonged presence of pCHK1Ser296 coincides with prolonged G2/M block and increased tumor cell survival. The relationship between (ATR)-CHK1 DNA damage response pathway and HMGA2 identifies a novel mechanism by which HMGA2 can alter DNA repair function in cancer cells. We identified HMGA2 as a novel factor contributing to temozolomide (TMZ) resistance in GB. HMGA2 knockdown sensitizes the GB cells to TMZ. We propose a specific combination of FDA-approved drugs, TMZ and Dovitinib (DOV), to increase GB cell death. We show that DOV downregulates key BER proteins, attenuates pSTAT3-coordinated Lin28A and HMGA2 expression. Our results suggest that a sequential therapeutic strategy of pretreating GB cells with DOV followed by a sequence of TMZ and DOV diminishes TMZ resistance and enhances the ability of TMZ to induce GB cell death. Overall, we identified HMGA2 as a multifunctional survival factor in human cancer cells and showed that targeting HMGA2 is a valid strategy to combat HMGA2+ cancer cells. / February 2016
6

Role of High Mobility Group A2 (HMGA2) in Prostate Cancer

Hawsawi, Ohuod 20 May 2019 (has links)
High mobility group A2 (HMGA2) is a non-histone protein highly expressed during the development but is low or absent in most adult tissues. Epithelial-mesenchymal transition (EMT) plays a critical role in prostate cancer progression and metastasis. HMGA2 has been shown to promote EMT in separate studies. Interestingly, wild-type HMGA2 and truncated (lacking the 3’UTR) HMGA2 isoforms are overexpressed in many cancers. However, there are no studies on the role of each isoform in prostate cancer progression. We hypothesized that wild-type and truncated HMGA2 promotes prostate cancer progression by different mechanisms. We analyzed the expression of HMGA2 in the prostate panel by western blot analysis and the localization in prostate tissue microarray by immunohistochemistry. We stably overexpressed wild-type and truncated HMGA2 cDNA in LNCaP cells and measured the expression and the localization of HMGA2 as well as EMT markers. We also performed the migration and cell viability assays. We analyzed phospho-ERK in cells overexpressing HMGA2 as well as inhibition with U0126 (MAPK inhibitor). To explore the role of truncated HMGA2, we measured the reactive oxygen species (ROS) concentration by DCFDA dye, as well as analyzing Jun-D as a putative downstream effector of HMGA2. Additionally, we knocked down Jun-D and performed the migration and cell viability assays. We treated ARCaP-M mesenchymal cells with camalexin, a 3-thizol-2-yl-indole (a natural product, as a candidate to target HMGA2) in vitro and in vivo in nude mice. Our results showed an increase in nuclear HMGA2 expression with prostate cancer progression as compared to normal tissue. LNCaP cells overexpressing wild-type but not truncated HMGA2 displayed nuclear localization and induced EMT via the ERK1/2 pathway, and this effect could be reversed by treating the cells with U0126. Conversely, truncated HMGA2 displayed cytoplasmic expression and increased prostate cancer migration via increasing Jun-D expression and ROS; this could be antagonized by Jun-D knockdown. Finally, treating ARCaP-M aggressive prostate cancer cells with camalexin reduce its expression in vitro and in vivo. In conclusion, both wild-type and truncated HMGA2 induce prostate cancer progression by different mechanisms which may be targeted by camalexin.
7

Gene Expression in Embryonic Chick Heart Development

Sneesby, Kyra, n/a January 2003 (has links)
Establishment of the biochemical and molecular nature of cardiac development is essential for us to understand the relationship between genetic and morphological aspects of heart formation. The molecular mechanisms that underly heart development are still not clearly defined. To address this issue we have used two approaches to identify genes involved in early chick cardiac development. Differential display previously conducted in our laboratory led to the identification of two gene fragments differentially expressed in the heart that are further described in this thesis. The full-length cDNA sequence of both eukaryotic translation initiation factor-2b (eIF-2b) and NADH cytochrome b5 reductase (b5R) were isolated using library screening. The upreglation of these genes during heart development is expected given the heart is the first functional organ to form in vertebrates and protein synthesis and cell metabolism at this stage of development is maximal. Limitations in the differential display approach led to the development and optimisation of a subtractive hybridisation approach for use with small amounts of cells or tissue. To focus on cardiac gene expression during the initial phases of heart development, subtractive hybridization was performed between the cardiogenic lateral plate mesoderm of Hamburger and Hamilton stage 4 embryos and the heart primordia of stage 9 embryos. Of the 87 independent clones identified by this procedure, 59 matched known sequences with high homology, 25 matched unknown expressed sequence tag (EST) sequences with high homology, and 3 did not match any known sequence on the database. Known genes isolated included those involved in transcription, translation, cell signalling, RNA processing, and energy production. Two of these genes, high mobility group phosphoprotein A2 (HMGA2) and C1-20C, an unknown gene, were chosen for further characterisation. The role of each gene in early chick heart development and indeed development in general, was addressed using techniques such as in situ hybridisation, transfection analysis, in ovo electroporation and RNAi. HMGA2 is a nuclear phosphoprotein commonly referred to as an architectural transcription factor due to its ability to modulate DNA conformation. In keeping with this function, HMGA2/GFP fusion protein was shown to localise to the nucleus and in particular, the nucleolus. In situ hybridisation analysis suggested a role for HMGA2 in heart and somite development. HMGA2 expression was first detected at HH stage 5 in the lateral plate mesoderm, a region synonymous with cells specified to the cardiac fate. HMGA2 was also strongly expressed in the presomitic segmental plate mesoderm and as somites developed from the segmental plate mesoderm, the expression of HMGA2 showed an increasingly more restricted domain corresponding to the level of maturation of the somite. Restriction of HMGA2 expression was first detected in the dorsal region of the epithelial somite, then the dorsomedial lip of the dermomyotome, and finally the migrating epaxial myotome cells. The novel intronless gene, C1-20C, predicts a protein of 148 amino acids containing a putative zinc finger binding domain and prenyl binding motif. Zinc binding assays showed that the zinc finger domain of C1-20C/MBP fusion protein bound over six times the quantity of zinc compared to MBP alone, although not in a 1:1 stoichiometric molar ratio. C1-20C/GFP fusion protein was shown to localise to as yet unidentified intracellular cytoplasmic vesicular compartments. These compartments did not colocalise with the endosome/lysosome pathway, aparently ruling out a role for C1-20C in protein trafficking, recycling or degradation. Expression of C1-20C in the chick embryo suggests a possible role in heart and notochord development and preliminary results using siRNA suggest that C1-20C is involved in normal heart looping.
8

The genetic basis for adaptation in natural populations

Lamichhaney, Sangeet January 2016 (has links)
Many previous studies in evolutionary genetics have been based on few model organisms that can be reared at ease in the laboratory. In contrast, genetic studies of non-model, natural populations are desirable as they provide a wider range of adaptive phenotypes throughout evolutionary timescales and allow a more realistic understanding of how natural selection drives adaptive evolution. This thesis represents an example of how modern genomic tools can be effectively used to study adaptation in natural populations. Atlantic herring is one of the world’s most numerous fish having multiple populations with phenotypic differences adapted to strikingly different environments. Our study demonstrated insignificant level of genetic drift in herring that resulted in minute genetic differences in the majority of the genome among these populations. In contrast, a small percentage of the loci showed striking genetic differentiation that were potentially under natural selection. We identified loci associated with adaptation to the Baltic Sea and with seasonal reproduction (spring- and autumn-spawning) and demonstrated that ecological adaptation in Atlantic herring is highly polygenic but controlled by a finite number of loci. The study of Darwin’s finches constitutes a breakthrough in characterizing their evolution. We identified two loci, ALX1 and HMGA2, which most likely are the two most prominent loci that contributed to beak diversification and thereby to expanded food utilization. These loci have played a key role in adaptive evolution of Darwin’s finches. Our study also demonstrated that interspecies gene flow played a significant role in the radiation of Darwin’s finches and some species have a mixed ancestry. This thesis also explored the genetic basis for the remarkable phenotypic differences between three male morphs in the ruff. Identification of two different versions of a 4.5 MB inversion in Satellites and Faeders that occurred about 4 million years ago revealed clues about the genetic foundation of male mating strategies in ruff. We highlighted two genes in the inverted region; HSD17B2 that affects metabolism of testosterone and MC1R that has a key role in regulating pigmentation, as the major loci associated with this adaptation.

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