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1
De, Rosa Maria Caterina. « Studio dell’espressione di geni coinvolti in pathways metabolici regolati da nutrienti ». Doctoral thesis, Universita degli studi di Salerno, 2015. http://hdl.handle.net/10556/1864.
Texte intégralRésumé :
2014-2015Il profilo sierico, con particolare riferimento ai livelli di biomarkers, rappresenta uno strumento efficace ed affidabile per la diagnosi di malattie metaboliche, come il diabete o le malattie cardiovascolari. La composizione del siero è influenzata sia dal metabolismo endogeno che dall’apporto nutrizionale. In effetti, lo stile alimentare, con particolare riferimento alla qualità e alla quantità dell’apporto nutrizionale, può fortemente influenzare il rischio e la progressione di malattia, poiché alcuni nutrienti agiscono come composti bioattivi. A questo proposito, la letteratura attuale indica un importante ruolo di specifiche molecole nutrizionali provenienti dalla dieta che interessano specifiche vie metaboliche. L'obiettivo del nostro progetto è quello di individuare pathways metabolici regolati da nutrienti, con lo scopo di identificare possibili taget terapeutici in stati patologici. [ a cura dell'autore]
XIII n.s.
2
Saada-Bouzid, Esma. « Étude génomique et fonctionnelle de la dérégulation du gène HMGA2 dans les tumeurs adipocytaires ». Thesis, Nice, 2015. http://www.theses.fr/2015NICE4000/document.
Texte intégralRésumé :
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 différenciéesBenign 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
3
Alvarado, Cárdenas Marcelo. « Estatinas y autoimnunidad. métodos de detección e importancia de los anticuerpos anti-HMGCR ». Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/666849.
Texte intégralRésumé :
Los inhibidores de la 3-hidroxi-3-metilglutaril coenzima A reductasa (HMGCR), conocidos como estatinas, son los fármacos más utilizados en el tratamiento de la hipercolesterolemia y en la prevención tanto primaria como secundaria de enfermedades cardiovasculares y asociadas a aterosclerosis. A pesar de que son bien tolerados por la mayoría de los pacientes y de tener un perfil muy seguro, algunos pacientes presentan ciertos efectos adversos entre los que destacan las alteraciones musculares.
La descripción reciente de una forma de toxicidad muscular inmunomediada asociada a anticuerpos dirigidos contra la enzima 3-hidroxi-3-metilglutaril coenzima A reductasa (anti-HMGCR), sustrato frente al que actúan las estatinas, implica a estos fármacos como responsables en parte de fenómenos autoinmunes asociados a la administración del fármaco.
Los objetivos de esta Tesis Doctoral, están encaminados a establecer la prevalencia de estos anticuerpos en la población general tratada con estatinas, pero también en enfermedades autoinmunes, entre las que las miopatías inflamatorias –por estar incluida la miopatía necrosante inmunomediada en el grupo- y las hepatitis autoinmunes –por explorar la reproducibilidad del modelo tóxico-inmunológico atribuido a la miopatía necrosante inmunomediada por estatinas- tienen una especial relevancia.
En estos estudios se ha podido comprobar que la prevalencia en la población general es inferior al 1%, tal y como otros grupos han publicado, y que en los pacientes con enfermedades autoinmunes la prevalencia es también baja, con la salvedad de las miopatías inflamatorias, en las que aumenta a expensas de las formas relacionadas con las estatinas (miopatía necrosante inmunomediada). No se ha conseguido reproducir el modelo en los pacientes con hepatitis autoinmune. Otros grupos a estudio, como las dislipemias familiares graves o la prevención secundaria del ictus, que contemplan la administración de estatinas a dosis altas han mostrado también una muy baja prevalencia.
La determinación de los anticuerpos anti-HMGCR es un punto relevante de estudio de estos pacientes, por lo que en esta Tesis se ha explorado la reproducibilidad y fiabilidad de dos técnicas de ELISA –una realizada en nuestro laboratorio (in-house) y otra comercial- observando una excelente concordancia entre ambas. Así mismo se ha descrito un nuevo patrón de inmunofluorescencia indirecta en triple tejido (HALIP), característico de estos autoanticuerpos, y que facilita su diagnóstico por su simplicidad y posibilidad de realización en la mayoría de laboratorios
Finalmente, se ha establecido un algoritmo diagnóstico-terapéutico sobre la actitud a tomar ante pacientes que reciben terapia con estatinas y presentan alteraciones musculares.Drugs that inhibit the enzyme, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), known as statins, are one of the most widely used medications. Statin use is associated with reductions in cardiovascular risk and mortality due to cardiovascular disease. Muscle toxicity is recognized as the main adverse effect of these drugs. Recently, an immune-mediated muscle toxicity associated with antibodies against HMGCR has been described. It means a possible statins-related autoimmune mechanism of toxicity. The aims of this Doctoral Thesis include the study of the prevalence of these anti-HMGCR antibodies in patients from the community treated with statins, but also the prevalence of anti-HMGCR antibodies in patients with different autoimmune diseases, especially in idiopathic inflammatory myopathies –given that immune-mediated necrotizing myopathy belongs to the group- and in autoimmune hepatitis –in order to examine the reproducibility of the well-known toxic-immunologic model of immune-mediated necrotizing myopathy. Data obtained from these studies shown that prevalence in patients from the community treated with statins was less than 1%, and similar data was obtained in patients with autoimmune diseases. Only patients with idiopathic inflammatory myopathies, because of the inclusion of patients with statin-associated immune-mediated necrotizing myopathy, showed a higher prevalence. On the other hand we failed to demonstrate that patients with autoimmune hepatitis were positive to these anti-HMGCR antibodies. We also studied other groups of patients, such as those with severe familiar dyslipidemia and those in secondary prevention after a cerebrovascular event, treated with high doses of statins, but the prevalence was again less than 1%. Method for anti-HMGCR detection is a relevant issue in the study of these patients. Thus, one of the points addressed in this Doctoral Thesis was to study de reproducibility and concordance of different test. Both ELISA test, in-house and commercial showed an excellent concordance. Moreover, a distinct and characteristic immunofluorescence pattern on triple rat tissue not previously described, that we called HALIP (HMGCR Associated Liver IFL Pattern) was found. This pattern would help to identify patients with statin-associated autoimmune myopathy in a standard laboratory setting. A practical approach to establish clinical recommendations regarding the muscle complaints related to statin use is reported as an algorithm at the end of the Doctoral Thesis.
4
Crabbe, T. B. « Studies on the adenylate cyclase and HMGCoA reductase of the yeast Saccharomyces cerevisiae ». Thesis, University of Liverpool, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233812.
Texte intégral
5
Wei, Linxuan, Xiaolin Liu, Wenjing Zhang, Yuyan Wei, Yingwei Li, Qing Zhang, Ruifen Dong et al. « Overexpression and oncogenic function of HMGA2 in endometrial serous carcinogenesis ». E-CENTURY PUBLISHING CORP, 2016. http://hdl.handle.net/10150/614759.
Texte intégralRésumé :
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.
6
Hawsawi, Ohuod. « Role of High Mobility Group A2 (HMGA2) in Prostate Cancer ». DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2019. http://digitalcommons.auctr.edu/cauetds/184.
Texte intégralRésumé :
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
Aktürk, Onur Altuntaş İrfan. « Hiperkolesterolemi oluşturulan ratlarda, HMGCoA redüktaz inhibitörü ilaçlarla (Statinler) tedavinin hipokampal NMDA reseptörü subunitlerine etkisi / ». Isparta : SDÜ Tıp Fakültesi, 2006. http://tez.sdu.edu.tr/Tezler/TT00294.pdf.
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Eisa-Beygi, Shahram. « HMGCR Pathway Mediates Cerebral-Vascular Stability and Angiogenesis in Developing Zebrafish ». Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/26112.
Texte intégralRésumé :
Intracerebral hemorrhage (ICH) is a severe form of stroke, with a high mortality rate and often resulting in irreversible neurological deterioration. Although animal studies have provided insight into the etiology of the disease, many of the causative genes and mechanisms implicated in cerebral-vascular malformations are unknown. Treatment options remain ineffective. With the present models, the pathophysiological consequences of ICH can only be assessed in situ and after histological analysis. Furthermore, common deficiencies of the current models include the heterogeneity, low expression and low reproducibility of the desired phenotype. Hence, there is a requirement for novel approaches to model ICH pathogenesis. Zebrafish (Danio rerio) has gained recognition as a vertebrate model for stroke research.
Through a combination of pharmacological blockers, metabolite rescue, genetic approaches, and confocal imaging analysis, I demonstrate a requirement for the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway in regulating developmental cerebral-vascular stabilization. A transient loss in HMGCR function induces ICH, characterised by progressive dilation of blood vessels, vascular permeability and vessel rupture. These effects are likely due to reduced prenylation of Rho GTPases, evidenced by morpholino-mediated blocking of the prenylation pathway and in vivo assessment of endothelial-specific localization of cdc42, a Rho GTPase family protein. These results are in conformity with recent clinical and experimental evidence.
I have further shown that this model consistently replicates common pathoghysiological processes associated with ICH. The hemorrhages are associated with the disruption of the blood-brain barrier, vessel disintegration, hematoma expansion and edema into the adjacent brain regions. Also, enhanced apoptosis, activation of inflammatory mediators in the periphery of the hematoma, enriched heme oxygenase 1 (HO-1) expression and localised thrombosis were observed in these embryos. I show that the patterning and distribution of catecholaminergic neurons, response to sensory stimulus and swimming speed were impaired as a consequence of ICH.
These results suggest that HMGCR contributes to cerebral-vascular stabilisation through Rho GTPase mediated-signalling and that zebrafish can serve as a powerful paradigm for the systemic analysis of the etiological and pathophysiological underpinnings of ICH and can help establish the basis for future studies into screening for putative therapeutics and elucidating mechanisms aiding functional recovery.
9
Villazon-Gonzales, Claudia. « Influência de variantes do receptor de LDL e da HMGCoA redutase na resposta à atorvastatina ». Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-10062009-152818/.
Texte intégralRésumé :
A influencia dos polimorfismos genéticos de HMGCoA redutase (HMGCR) e LDL receptor (LDLR) na resposta a atorvastatina (10 mg/dia/4semanas) foi avaliada em individuos hipercolesterolemicos (HC). Amostras de sangue foram coletadas de 153 HC e 182 normolipidemicos (NL) para determinações de lipideos séricos e extração de DNA. Polimorfismos de troca única (SNP) HMGCR (A11898T e T24558G) e LDLR (C16730T, C20001T, G26857A) foram detectados. por PCR-RFLP. Os alelos HMGCR 11898T e 24558G foram associados com menores triglicérides e VLDL-C séricos nos grupos NL e HC (p<0,05). Além disso, o SNP HM0CR T24558G foi relacionado com HDL-C e apoAI séricos aumentados em resposta a atorvastatina no grupo HC. O alelo LDLR 20001 C foi associado com maior apoAI sérica basal no grupo NL (p=O,034) e com melhor resposta de apoAI a atorvastatina no grupo HC (p=O,045). Foi observada relação entre o haplótipo heterozigoto LDLR 20001 C/16730T e redução significativa de apoB e aumento de apoAI no soro após o tratamento com atorvastatina (p
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Annewanter, Franka Maria [Verfasser]. « Expression von TRAIL-Rezeptoren und HMGA2 im duktalen Pankreasadenokarzinom / Franka Maria Annewanter ». Kiel : Universitätsbibliothek Kiel, 2014. http://d-nb.info/1064306101/34.
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Mehtali, Abdel-Majid. « Les genes de maintenance : etude du gene hmgcoa reductase in vitro et dans les souris transgeniques ». Université Louis Pasteur (Strasbourg) (1971-2008), 1988. http://www.theses.fr/1988STR13162.
Texte intégralRésumé :
Les genes de maintenance sont exprimes de maniere ubiquitaire par un mecanisme encore incompris. Pour aborder ce probleme, les auteurs ont choisi comme modele d'etude un gene de maintenance typique, le gene de l'hydroxymethylglutaryl coa reductase (hmgcr), enzyme cle de la biosynthese du cholesterol. Le gene hmgcr de souris a ete isole et sa region promotrice caracterisee; l'expression et le profil de methylation de plusieurs genes chimeriques, dans lesquels le gene marqueur cat est sous le controle de sequences promotrices hmgcr de taille decroissante, ont ete etudies in vitro (par transformation de cellules en culture) et in vivo (dans les souris transgeniques)
12
Wang, Hui, et 王晖. « Overexpression of wild-type and mutant BjHMGS1 in transgenic model plants and analysis on the Arabidopsis hmgs/HMGS mutant ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hdl.handle.net/10722/198807.
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13
Natarajan, Suchitra. « Roles of high mobility group AT-hook protein 2 (HMGA2) in human cancers ». Elsevier, 2013. http://hdl.handle.net/1993/31092.
Texte intégralRésumé :
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
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INGRAHAM, SUSAN ELIZABETH. « THE BALANCED, RECIPROCAL TRANSLOCATION OF CHROMOSOMAL SUBBANDS 12q15 AND 14q24 AND ALTERED GENE EXPRESSION IN UTERINE LEIOMYOMA ». University of Cincinnati / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1029433658.
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Arouche-Delaperche, Louiza. « Effet des auto-anticorps anti-SRP et anti-HMGCR sur le muscle strié squelettique ». Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066389/document.
Texte intégralRésumé :
Les myopathies nécrosantes auto-immunes (MNAI) appartiennent au groupe des myopathies inflammatoires idiopathiques. Les MNAI sont des maladies musculaires sévères pouvant conduire à un déficit musculaire définitif et handicapant. Pour rétablir une force normale et prévenir le handicap, des traitements prolongés associant corticothérapie et immunosuppresseurs sont nécessaires. Les MNAI sont définies histologiquement par la prédominance de fibres musculaires en nécrose qui contraste avec l’absence ou la faible abondance d'inflammation musculaire. Les mécanismes impliqués dans la nécrose comme ceux impliqués dans les séquelles atrophiques sont en revanche inconnus. Les MNAI peuvent être associées à des auto-anticorps (aAc) soit anti-SRP, soit anti-HMGCR. Ces aAc ciblent des protéines cytoplasmiques ubiquitaires. Leurs titres sont corrélés avec l'activité de la maladie, suggérant ainsi le rôle pathogène de ces aAc. Dans ce travail de thèse, nous avons émis l’hypothèse que les aAc pouvaient être impliqués dans les lésions musculaires observées aux cours des MNAI anti-SRP+ et anti-HMGCR+. Durant cette étude, nous avons eu pour objectifs : (i) de caractériser et de quantifier la nécrose musculaire et l’inflammation associée, ainsi que les mécanismes physiopathologiques impliqués (rôle des aAc) ; (ii) d’analyser la régénération et l’atrophie musculaire et l’effet des aAc sur ces phénomènes. L'analyse histologique des biopsies musculaires des patients MNAI a montré que la proportion des fibres musculaires en nécrose était plus importante chez les patients anti-SRP+. Les taux sériques de créatine phosphokinase étaient corrélés avec la proportion de fibres nécrotiques, montrant ainsi que ce taux est un bon marqueur de l’activité de la maladie. De façon inattendue, une inflammation musculaire était régulièrement observée. En particulier, la densité lymphocytaire T était dans un quart des cas comparable à celle des autres myopathies inflammatoires. Cette densité cellulaire était de plus corrélée au pourcentage de fibres en nécrose. L’infiltrat inflammatoire était néanmoins composé principalement de macrophages. Des macrophages CD68+ iNOS+, impliqués dans des phénomènes de myophagocytoses dans un environnement Th-1 étaient régulièrement observés. Des macrophages avec un phénotype suggérant une activation alternative par l’immunité humorale ont aussi été observés. Dans ce sens, la présence de dépôts de complexe d’attaque membranaire à la surface des fibres musculaires, mais aussi des dépôts de C1q et d’IgG montraient l’activation de la voie classique du complément au cours des MNAI. De plus, la détection des protéines SRP et HMGCR sur certaines fibres musculaires immatures (in vitro et in vivo) suggérait le rôle pathogène des aAc. Concernant les mécanismes de régénération et les phénomènes d’atrophie musculaire, l’analyse des biopsies musculaires a révélé l’importance de l’irrégularité du diamètre des fibres avec une prédominance de petites fibres. Ces petites fibres correspondaient à la fois à des fibres en régénération et à des fibres en nécrose. In vitro, les Ac anti-SRP et anti-HMGCR induisent une atrophie musculaire en augmentant la transcription de MAFbx et Trim63. En outre, l'atrophie des fibres musculaires a été associée à un niveau élevé de cytokines inflammatoires comme TNF, IL-6 et ROS. Concernant l’étude de la régénération musculaire, in vitro, la présence des aAc réduisait la fusion des myoblastes. Ce défaut était associé à une diminution de la production de cytokines anti-inflammatoires IL-4 et IL-13. L’ajout d'IL-4 et/ou d’IL-13 permettait de corriger la fusion des myoblastes. Dans ce travail, les données recueillies convergent pour suggérer le rôle pathogène des aAc anti-SRP et anti-HMGCR dans les lésions musculaires nécrotiques mais aussi dans la régénération musculaire et l’atrophie. Ces données nouvelles soulignent l’importance de traitements ciblés au cours des MNAIImmune mediated necrotizing myopathy (IMNM) is recognized as a separate entity among inflammatory myopathies. IMNM is a severe disabling muscle disease requiring prolonged combination of corticosteroid and immunosuppressive drugs. IMNM is morphologically defined by predominant muscle fiber necrosis and no or little inflammation, and is associated with important variation of the size of the fiber. However pathogenic mechanisms involved in muscle necrosis and muscle atrophy are largely unknown. IMNM may be associated with either anti-SRP or anti-HMGCR auto-antibodies (aAbs). The titer of these aAbs, targeting ubiquitous cytoplasmic proteins, is correlated with the disease activity suggesting their pathogenic role. In this thesis, we described the morphology of skeletal muscle alterations occurring in both conditions of anti-SRP+ or anti-HMGCR+ patients, studied the role of the Abs in (i) the necrosis mechanisms and the associated inflammation; (ii) by analyzing the atrophy and the regeneration mechanisms. Muscle histological analysis of anti-SRP+ and anti-HMGCR+ patients showed a random distribution of necrotic fibers that was more pronounced in anti-SRP+ patients. Creatine Phosphokinase levels; myolysis indicator, and muscle regeneration were correlated with the proportion of necrotic fibers. Inflammation was regularly observed in IMNM muscle patients. Macrophages were the most abundant but T cells densities were in a quarter of cases in the same range as myositis controls. CD68+iNOS+ macrophages and a Th-1 immune environment were also observed and involved in ongoing myophagocytosis. Of note, macrophages with alternative activation were also detected. Humoral immunity with activation of the classical pathway of the complement cascade was observed in IMNM. Positive membrane staining for SRP and HMGCR proteins, on some muscle fibers, was detected both in vitro and in muscle biopsies of IMNM patients. An important proportion of small fibers corresponding to both atrophic and regenerating fibers was observed in anti-SRP+ and anti-HMGCR+ patients. In vitro, anti-SRP and anti-HMGCR aAbs induced muscle fibers atrophy and increased the transcription of MAFbx and Trim63. In addition, the muscle fiber atrophy was associated with high level of inflammatory cytokines such TNF, IL-6 and ROS. Muscle regeneration in vitro was also affected by impairing the myoblasts fusion in presence of anti-SRP and anti-HMGCR Abs. This default was associated with a decrease production of anti-inflammatory cytokines: IL-4 and IL-13. Of note, the addition of IL-4 and/or IL-13 totally rescued the fusion. Together those data suggest that these aAbs have a pathogenic effect on muscle. Anti-SRP and anti-HMGCR are involved in muscle atrophy and affect the regeneration. The role of these aAbs in muscle damages occurring in IMNM was highlighted and emphasizes the potential interest of targeted therapies
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Junit, Sarni Mat. « Regulation of human HMGCoA reductase and LDL receptor gene expression in relation to coronary heart disease and diet ». Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387665.
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Mehtali, Abdel-Majid. « Les Gènes de maintenance étude du promoteur du gène HMGCoA réductase in vitro et dans les souris transgéniques / ». Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb376161082.
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Andrieux, Joris. « Anomalies cytogénétiques et moléculaires des myélofibroses avec métaplasie myéloi͏̈de : dérégulation et hyperexpression du gène HMGA2 ». Lille 2, 2003. http://www.theses.fr/2003LIL2MT21.
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Bastos, Guilherme de Medeiros. « Detecção de proteínas envolvidas no remodelamento da cromatina de embriões bovinos produzidos in vitro a partir de oócitos oriundos de folículos antrais pequenos e grandes ». Universidade Federal de Santa Maria, 2006. http://repositorio.ufsm.br/handle/1/4138.
Texte intégralRésumé :
It has been demonstrated that oocytes of several species acquire the capacity to complete
meiotic maturation and support early embryonic development during the final stages of follicular growth.
Aiming to investigate molecular differences between bovine embryos produced from oocytes derived
from small (1 to 2-mm) and large (4 to 8-mm) follicles, two experiments were designed to evaluate by
immunocytochemistry the presence on chromatin of three regulatory factors involved mainly in DNA
transcription and repair. In the first experiment, we evaluated whether the expression pattern of the High-
Mobility Group N2 (HMGN2) and acetylated histone H3 Lysine 14 (Ac.H3K14) were affected by the
origin (from small vs. large follicles) and time of first cleavage (< 24 h vs. > 24 h) of parthenogenetically
activated (PA) oocytes. Early (until 24 hr) and late (after 24 hr) cleaved embryos were fixed at 36, 50, 60,
70 and 80 h after PA and processed to detect HMGN2 or Ac.H3K14. The rate of nuclear maturation
(81% vs. 59%), early cleavage (47% vs. 39%), and blastocyst (34% vs. 19%) were significantly higher
(P<0.05) in oocytes from large compared to small follicles. The rate of Ac.H3K14 (61% vs. 38%) and
HMGN2 (74% vs. 56%) positively stained nuclei at 60 h post PA was higher (P<0.05) in embryos
derived from small compared to large follicles. However, more HMGN2 positively stained nuclei (94%
vs. 75%; P<0.05) were detected in embryos from large follicles at 80 h post PA. We concluded that the
temporal proportion of embryonic nuclei with positive signal to HMGN2 and Ac.H3K14 is affected by
both follicle size and time to complete first cleavage of oocytes. In the second experiment, we
investigated whether the expression pattern of the phosphorylated histone H2A.X (γH2A.X) protein,
which is an indicator of DNA double-strand breaks, is different in embryos produced from oocytes
derived from small or large follicles. Oocytes were PA or in vitro fertilized (IVF) for 18 h and then
cultured. Cleavage was assessed at 24 and 36 h after PA and at 32 and 42 h after IVF. Cleaved embryos
were fixed at 36 h after PA and 42 h after IVF, and then processed to detect the γH2A.X. Most of the
cleaved embryos produced from PA and IVF oocytes had detectable amounts of γH2A.X, ranging from
few foci to a complete diffuse staining of the nuclei. γH2A.X was detected in 64% vs. 76% (P<0.05) of
nuclei in PA embryos and in 76% vs. 80% (P>0.05) of nuclei in IVF embryos produced from oocytes
derived from small and large follicles, respectively. IVF embryos presenting less than 4 nuclei at 42 h
showed higher rates (P<0.05) of γH2A.X positive nuclei (89% and 85%) than those with ≥4 nuclei (72%
and 62%, for large and small follicles, respectively). We found that γH2A.X is highly detected but not
differently expressed in early bovine embryos produced from PA and IVF oocytes derived from small
and large follicles. In general, the present experiments demonstrate that HMGN2, Ac.H3K14 and
γH2A.X proteins are expressed during early bovine embryogenesis.Tem sido demonstrado que oócitos de várias espécies adquirem capacidade para completar a maturação meiótica e suportar o desenvolvimento embrionário durante os estágios finais do crescimento folicular. Com o objetivo de investigar diferenças moleculares entre embriões bovinos produzidos a partir de oócitos derivados de folículos pequenos (1-2 mm) e grandes (4-8 mm), dois experimentos foram delineados visando identificar por imunocitoquimica a presença de três fatores reguladores da cromatina envolvidos principalmente nos processos de transcrição e reparo do DNA. No primeiro experimento, foi investigado se o perfil de expressão das proteínas (do inglês) High-Mobility Group N2 (HMGN2) e histona H3 acetilada na lisina 14 (Ac.H3K14) seria alterado pela origem dos oócitos (folículos pequenos vs. folículos grandes) e pelo tempo necessário para realizar a primeira clivagem (<24 h vs. >24 h) após ativação partenogenética (AP). Embriões clivados cedo (até 24 h) e tarde (após 24 h) foram fixados às 36, 50, 60, 70 e 80 h após AP e processados para detectar a HMGN2 ou Ac.H3K14. Os percentuais de maturação nuclear (81% vs. 59%), clivagem cedo (47% vs. 39%) e blastocisto (34% vs. 19%) foram significativamente maiores (P<0,05) nos oócitos oriundos de folículos grandes em comparação aos de folículos pequenos. Os percentuais de núcleos positivos para Ac.H3K14 (61% vs. 38%) e HMGN2 (74% vs. 56%) às 60 h após AP foram maiores (P<0,05) nos embriões produzidos a partir de oócitos de folículos pequenos comparado aos de folículos grandes. Entretanto, um maior percentual de núcleos positivos para HMGN2 (94% vs. 75%; P<0,05) foi detectado em embriões produzidos com oócitos de folículos grandes às 80 h após a AP. Concluiu-se que a proporção de núcleos com sinal positivo para HMGN2 e Ac.H3K14 é dependente do tamanho dos folículos e do tempo transcorrido para os oócitos realizarem a primeira clivagem. No segundo experimento, foi investigado se o perfil de fosforilação da proteína histona H2A.X (γH2A.X), que é um indicador de rompimento da cadeia dupla do DNA, seria diferente em embriões produzidos a partir de oócitos oriundos de folículos pequenos ou grandes. Os oócitos foram submetidos à AP ou fertilização in vitro (FIV) por 18 h e, então, cultivados. A clivagem foi avaliada 24 e 36 h após a AP e 32 e 42 h após FIV. Os embriões clivados foram fixados 36 h após AP e 42 h após FIV, e então processados para detectar a presença da γH2A.X. A maioria dos embriões produzidos a partir de oócitos submetidos à AP e FIV apresentou quantidades detectáveis de γH2A.X, variando entre poucos focos até um sinal completamente difuso no núcleo. A γH2A.X foi detectada em 64% vs. 76% (P<0,05) dos núcleos dos embriões ativados e em 76% vs. 80% (P<0,05) dos núcleos dos embriões de FIV produzidos a partir de oócitos oriundos de folículos pequenos e grandes, respectivamente. Embriões oriundos de FIV que apresentaram número <4 núcleos às 42 h tiveram maiores percentuais (P<0,05) de núcleos positivos para γH2A.X (89% e 85%) do que os que apresentaram número ≥4 núcleos (72% e 62%, respectivamente para folículos pequenos e grandes). Foi demonstrado que a γH2A.X é altamente detectada mas não é diferentemente expressa em embriões bovinos produzidos a partir de oócitos oriundos de folículos pequenos e grandes e submetidos à AP ou FIV. Em geral, os experimentos demonstraram que as proteínas HMGN2, Ac.H3K14 e γH2A.X são expressas durante o desenvolvimento embrionário precoce em bovinos.
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Tan, E.-Jean. « Transcriptional and Epigenetic Regulation of Epithelial-Mesenchymal Transition ». Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-206120.
Texte intégralRésumé :
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.
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Rehbini, Ohoud Mohammedsabri M. « The role of high mobility nucleosomal binding protein (Hmgn2) in undifferentiated mouse epiblast carcinoma stem cells ». Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7190/.
Texte intégralRésumé :
High mobility group nucleosome binding (HMGN) proteins belong to the superfamily of high mobility group (HMG) proteins. HMGN1 and HMGN2 are ubiquitously expressed in all vertebrates, and are most highly expressed in embryonic tissue. Moreover, HMGN1 and HMGN2 were found to be highly expressed in neural stem/progenitor cells in the mouse brain. Here, mouse embryonal carcinoma cells (P19 EC) were used as a model system to study the role of HMGN proteins in pluripotent stem cells. Previously, experiments using short interfering RNA (siRNA) technology to knockdown HMGN1 and HMGN2 have suggested that HMGN proteins are important for the expression of key pluripotent genes, Oct4, Sox2 and Nanog, in P19 EC cells (Mohan, 2012). The aim of this thesis was to develop a lentiviral system for the long term knockdown of Hmgn2, in order to investigate more fully the role of this protein in stem cell pluripotency and differentiation. Constitutive and inducible lentiviral shRNAmir systems were tested and optimized, and a constitutive system was chosen for further work. HMGN2 knockdown in undifferentiated P19 EC cells resulted in the down-regulation of Oct4 protein levels. ChIP assays showed that HMGN2 binding over the Oct4 gene was absent in HMGN2 knockdown cells. Furthermore, binding of HMGN1 at this locus was increased in the absence of HMGN2. Consistent with the reduction in Oct4 expression, levels of the active histone modification, H3K4me3, were also decreased at the Oct4 gene. These results support a role for HMGN2 in the regulation of Oct4 expression in P19 cells, and imply that HMGN2 may be important for maintaining stem cell pluripotency.
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Bergua, Cecile. « Pathogénicité des auto-anticorps anti-SRP et anti-HMGCR au cours des myopathies nécrosantes auto-immunes ». Thesis, Normandie, 2017. http://www.theses.fr/2017NORMR067/document.
Texte intégralRésumé :
Les myopathies auto-immunes (MAI), classiquement appelées myosites ou myopathies inflammatoires idiopathiques, représentent un groupe de maladies définies par des caractéristiques cliniques, histopathologiques et biologiques. Une des caractéristiques les plus notables est la présence d’auto-anticorps (aAc) chez environ 60% des patients. Les MAI regroupent : les dermatomyosites, les polymyosites, les myosites à inclusion, les myosites de chevauchement incluant le syndrome des anti-synthétases et les myopathies nécrosantes auto-immunes (MNAI). Les MNAI ont été récemment individualisées parmi les MAI comme des maladies graves fréquemment associées à la présence d’aAc dirigés contre la Signal Recognition Particle (SRP) ou la 3-Hydroxy-3-MéthylGlutaryl-CoA Réductase (HMGCR). La localisation de SRP et HMGCR étant intracellulaire, le rôle des aAc dans la physiopathologie des MNAI reste mal compris. La pathogénicité des aAc anti-SRP et anti-HMGCR envers des cellules musculaires cultivées in vitro a récemment été mise en évidence mais leurs effets in vivo demeurent inconnus.Au cours de cette thèse, j’ai étudié le rôle physiopathologique des aAc anti-SRP et anti-HMGCR in vivo chez la souris. Le transfert passif d’IgG de patients atteints de MNAI, positifs pour les aAc anti-SRP ou anti-HMGCR, à la souris sauvage entraîne un déficit musculaire. Ce déficit était prolongé chez la souris immunodéficiente Rag2-/-, et limité chez la souris déficiente pour la fraction C3 du complément. Chez les souris recevant les IgG anti-SRP+, le déficit musculaire était important et accompagné de quelques signes de nécrose myocytaire. Les IgG anti-HMGCR+ induisaient une faiblesse musculaire moindre, et des signes histopathologiques rares ou absents. Ces résultats sont en accord avec l’observation chez l’homme d’une maladie plus grave chez les patients anti-SRP+ par rapport aux patients anti-HMGCR+. La supplémentation en complément humain des souris augmentait le déficit musculaire induit par les IgG anti-HMGCR+ et de façon moindre pour les IgG anti-SRP+. En collaboration avec l’INSERM UMRS974, nous avons montré que les cibles SRP et HMGCR peuvent être détectées à la surface des fibres musculaires in vitro, suggérant qu’elles puissent être accessibles aux aAc in vivo.Ces résultats démontrent pour la première fois le rôle pathogène des aAc anti-SRP et anti-HMGCR in vivo et l’implication du complément, contribuant à une avancée dans la compréhension de la physiopathologie des MNAIAutoimmune myopathies (AIM), classically called myositis or idiopathic inflammatory myopathies, represent a group of diseases characterized by clinical, histopathologic and biologic properties. One of the most notable properties is the presence of autoantibodies (aAb) in approximately 60% of patients. AIM includes five principal entities: dermatomyositis, polymyositis, inclusion body myositis, overlap myositis including the anti-synthetase syndrome and immune-mediated necrotizing myopathies (IMNM). IMNM have recently been individualized among AIM as severe diseases frequently associated with aAb directed against Signal Recognition Particle (SRP) or 3-Hydroxy-3-MethylGlutaryl-CoA Reductase (HMGCR). Since SRP and HMGCR have an intracellular localization, the role of anti-SRP and anti-HMGCR aAb in the pathophysiology of IMNM remains unclear. Anti-SRP and anti-HMGCR aAb were recently shown to be pathogenic to muscle cells in vitro but in vivo effects remain unknown.During this thesis, I studied the pathophysiological role of anti-SRP and anti-HMGCR aAb in vivo in mice. Passive transfer of IgG purified from plasma of IMNM patients positive for anti-SRP and anti-HMGCR aAb to wild-type mice elicited a muscle weakness. Immune-deficient Rag2-/- mice presented a prolonged muscle deficit, whereas complement component C3 deficient mice had limited signs. Mice injected with anti-SRP+ IgG displayed a strong muscle weakness with mild myocytic necrosis. The muscle deficit was milder and histopathologic findings were not always present in mice receiving anti-HMGCR+ IgG. This is in accordance with clinical findings in anti-SRP+ patients which present a more severe disease than anti-HMGCR+ patients. When supplemented with human complement, mice receiving anti-HMGCR+ IgG showed a more severe muscle deficit. This supplementation increased the deficit induced by anti-SRP IgG in a milder way. In collaboration with INSERM UMRS974, we showed that the targets SRP and HMGCR can be detected on the surface of myofibres in vitro, suggesting that they could be accessible to aAb in vivo.Together, these results demonstrate for the first time the pathogenic role of anti-SRP and anti-HMGCR aAb in vivo and the implication of complement, contributing to a progress in the comprehension of MNAI pathophysiology
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Roemer, Sarah Clark. « Structural and functional analysis of progesterone receptor-DNA interaction / ». Connect to full text via ProQuest. IP filtered, 2005.
Trouver le texte intégralRésumé :
Thesis (Ph.D. in Molecular Biology) -- University of Colorado at Denver and Health Sciences Center, 2005.Typescript. Includes bibliographical references (leaves 165-185). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Oliveira, Mateos Cristina. « Epigenetic regulation mediated by antisense non-coding RNAs and its impact on oncogenic pathways : the HMGA2/RPSAP52 locus ». Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/669259.
Texte intégralRésumé :
The vast majority of the human genome is transcribed giving rise to non-coding RNAs. Antisense transcripts are one of the most abundant types of long non-coding RNAs and many of them have regulatory roles in the transcription of the nearby genes. Specifically, we study gene pairs with divergent transcription and a GC skew in the promoter region that allows the formation of an R-loop by the antisense. The HMGA2/RPSAP52 pair was selected for further investigation due to the aberrant expression of HMGA2 in a multitude of cancers. In this case, the R-loop formed by RPSAP52 reduces chromatin compaction, which has a positive impact on HMGA2 transcription.
Both genes are overexpressed in some human cancers, with a positive correlation in breast cancer patients and cell lines; and hypermethylation of their promoter correlates with their repression. On the other hand, RPSAP52 enrichment in the cytoplasm, its polyadenylation and its association with polysomes indicate a possible function in translation. In this sense, we described the binding of RPSAP52 to IGF2BP2 protein, a transcriptional target of HMGA2 that regulates the translation of mRNAs such as IGF1R and RAS. RPSAP52 depletion resulted in an increase of let-7 expression that correlated with low levels of the proteins IGF2BP2, IGF1R and RAS, whose mRNAs are let-7 targets. LIN28B is not expressed in MCF10A cells and LIN28A does not change with RPSAP52 depletion. Thus, it is not possible to explain these results by alterations in the levels of LIN28 proteins, the main negative regulators of let-7 biogenesis.
The phenotypic impact of RPSAP52 depletion in breast cancer cell lines includes a decrease in cell proliferation, migration and clonogenicity. Also, the protein levels of the stemness markers NANOG and OCT4 are reduced in these cells. Similarly, the weight and volume of subcutaneous tumors is lower in immunosuppressed mice injected with RPSAP52-depleted cells.
Given the role played by the HMGA2-IGF2BP2-NRAS axis in embryonic rhabdomyosarcoma, the study was extended to sarcomas using A673 cell line as a model. As seen in MCF10A, an increase in let-7 expression was observed in RPSAP52-depleted clones, and the interaction between IGF2BP2 and RPSAP52 was confirmed. In this case, IGF2BP2 and RAS proteins remain unchanged, but the pathway is affected downstream
with the decrease of p-ERK. It is noteworthy to mention the reduction of LIN28B protein in the clones, which is abundantly expressed in A673 cells. The reduction in tumor formation was the consequence of RPSAP52 depletion in vivo.
Importantly, we described the binding of IGF2BP2 to LIN28B mRNA, and confirmed the interaction using iCLIP-Seq. RPSAP52 knockdown caused a specific loss of IGF2BP2 affinity for particular mRNAs, influencing the translational efficiency of HMGA2 and LIN28B. Moreover, RPSAP52 mediates IGF2BP2 recruitment to polysomes. This could be the mechanism by which RPSAP52 controls the expression of LIN28B and, therefore, let-7 levels.
An expression array was performed to study the genome-wide impact of RPSAP52 silencing. The increase of some tumor suppressor genes was detected in the clones, as well as the decrease of genes usually overexpressed in cancer. In support of the influence that RPSAP52 has in tumorigenicity, high expression levels imply a worse survival rate in sarcoma patients.
Our findings provide new knowledge about NATs-mediated regulatory mechanisms and highlight their impact on cancer-related genes and on tumor progression itself. According to our results, RPSAP52 regulates HMGA2 expression through the formation of an R-loop and IGF2BP2 function through the binding to this protein. We also demonstrated that LIN28B mRNA constitutes a new target of IGF2BP2. Thus, RPSAP52 affects LIN28B/let-7 balance and promotes tumorigenesis. In conclusion, our work establishes RPSAP52 as a master regulator with oncogenic properties.La gran mayoría del genoma humano se transcribe, dando lugar en muchos casos a RNAs no codificantes. Los transcritos antisentido son uno de los tipos más abundantes de RNAs no codificantes largos y muchos poseen importantes funciones en la regulación de los genes cercanos. Este es el caso de RPSAP52, transcrito antisentido del gen codificante HMGA2. La expresión de ambos genes es elevada en varios cánceres humanos y correlaciona positivamente como consecuencia de la regulación que RPSAP52 ejerce sobre HMGA2. RPSAP52 forma un R-loop en la región promotora de los dos genes, lo que modifica la conformación de la cromatina y favorece la transcripción de HMGA2. RPSAP52 desempeña funciones adicionales en el citoplasma gracias a su unión a la proteína IGF2BP2, cuya transcripción es regulada por HMGA2. IGF2BP2 promueve la traducción de genes relacionados con importantes rutas proliferativas, y su interacción con RPSAP52 afecta su unión a algunos RNAs mensajeros, así como su reclutamiento a polisomas. En este trabajo demostramos que LIN28B, uno de los principales reguladores negativos de la maduración del miRNA let-7, es uno de sus targets. De este modo, RPSAP52 aumenta la traducción de LIN28B y reduce los niveles del supresor tumoral let-7. La regulación mediada por RPSAP52 tiene un importante impacto en rutas génicas relacionadas con el cáncer. Su depleción afecta negativamente las características tumorigénicas de las células in vitro y disminuye la progresión tumoral in vivo. Además, RPSAP52 puede ser considerado como un biomarcador en sarcomas, ya que sus altos niveles se asocian a un peor pronóstico. En resumen, el presente trabajo propone un modelo regulador mediado por RPSAP52 con dos niveles diferentes de acción. Este transcrito antisentido promueve la activación transcripcional de HMGA2 y, a su vez, regula la función de la proteína IGF2BP2. Dado que HMGA2 e IGF2BP2 están en la misma vía proliferativa, RPSAP52 refuerza la función de HMGA2 tanto sobre IGF2BP2 como sobre sus efectores posteriores, lo que afecta la progresión del cáncer. Debido a los importantes roles desempeñados por RPSAP52 y a sus propiedades oncogénicas, podría ser una potencial diana terapéutica para el desarrollo de nuevos tratamientos contra el cáncer.
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Singh, Indrabahadur [Verfasser]. « HMGA2-mediated epigenetic regulation of Gata6 controls epithelial canonical WNT signaling during lung development and homeostasis / Indrabahadur Singh ». Gießen : Universitätsbibliothek, 2015. http://d-nb.info/107435513X/34.
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Schwarm, Frank [Verfasser]. « Expressionsanalyse und klinische Bedeutung des High-mobility Group AT-hook 2 Antigens (HMGA2) in humanen Glioblastomen / Frank Patrick Schwarm ». Gießen : Universitätsbibliothek, 2018. http://d-nb.info/1155405579/34.
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Kahli, Malik. « Implication des protéines HMGA et HMGA2 dans les changements du programme de réplication au cours de la sénescence cellulaire ». Thesis, Montpellier 2, 2011. http://www.theses.fr/2011MON20059/document.
Texte intégralRésumé :
La sénescence, considérée comme étant un arrêt irréversible du cycle cellulaire, se caractérise par des changements drastiques de l'expression génique et de l'organisation de la structure de la chromatine. En effet, il se forme des foyers denses d'hétérochromatine au sein du noyau (SAHF) et ces modifications s'accompagnent d'un déclin progressif de la capacité à dupliquer le génome. Au cours de ma thèse, j'ai voulu savoir si ces modifications de la chromatine induite par les SAHF pouvaient influer sur le programme de réplication et changer la distribution des origines de réplication sur le génome au cours du processus d'entrée en sénescence réplicative des cellules. Nous avons donc, dans un premier temps, comparé par peignage moléculaire de l'ADN réplicatif la distribution des origines de réplication de cellules primaires prolifératives et sénescentes. Nous avons également cartographié l'ensemble de leurs origines de réplication sur la totalité du génome en purifiant les brins naissants aux origines de réplication que nous avons couplé à une analyse de séquençage à haut débit.Les protéines HMGA1 et HMGA2 étant des éléments précurseurs essentiels à la mise en place des SAHF, nous avons créé des lignées cellulaires qui, en sur-exprimant de façon inductibles ces protéines, induit une sénescence prématurée. Nous avons réalisé le même type d'analyses sur ces cellules afin de mettre en évidence le rôle de ces protéines dans les modifications du programme de réplication que nous avons observé au cours de l'entrée en sénescence de ces différents types cellulairesSenescence, considered as an irreversible cell cycle arrest, is characterized by dramatic changes in genes expression and chromatin organisation forming dense heterochromatic foci (SAHF). These changes are concomitant to a progressive decline of the capactity to replicate the genome. My PhD topic was to investigate whether the chromatin changes induced by SAHF formation could influence the replication program and modify the origin distribution along the genome at replicative senescence. We first compared the origin distribution of proliferative and pre-senescent primary fibroblasts by DNA molecular combing. Then, we mapped the origins positions in whole human genome by using the nascent strand purification assay coupled to deep sequencing.As HMGA1 and HMGA2 proteins are essential to induce SAHF formation, we designed inducible cell lines wich overexpress these proteins, triggering premature senescence. We made the same type of experiments in these cell lines in order to investigate the implication of these proteins on the changes of the replication program we observed during senescence
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Schwarm, Frank Patrick [Verfasser]. « Expressionsanalyse und klinische Bedeutung des High-mobility Group AT-hook 2 Antigens (HMGA2) in humanen Glioblastomen / Frank Patrick Schwarm ». Gießen : Universitätsbibliothek, 2018. http://d-nb.info/1155405579/34.
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Weihrauch, Marc-Andreas Günter. « Butyrat moduliert die Expression der Nicht-Histon-Proteine HMGA1, HMGN1 und HMGN2 in humanen Adenokarzinomzellen des Kolons und des Magens ». [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=971750556.
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Sindi, Abdulmajeed Abdulghani A. « Investigating the role of HMGN2 in the self-renewal and neuronal differentiation of ECCs using the CRISPR-Cas9 knockout system ». Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8591/.
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Arazi, Simone Sorkin. « Efeitos de hipolipemiantes e polimorfismos sobre a expressão dos genes HMGCR, LDLR, SREBF1a, SREBF2, SCAP e NPC1L1 em indivíduos hipercolesterolêmicos ». Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-15012009-145201/.
Texte intégralRésumé :
A homeostase do colesterol é mediada por proteínas envolvidas na absorção (NPC1L1), regulação (SREBP1, SREBP2, SCAP), síntese (HMGCR) e remoção plasmática (LDLR). Os fármacos inibidores da síntese (vastatinas) e absorção (ezetimiba) do colesterol são potentes agentes hipocolesterolemiantes. Alterações em vários genes têm sido associadas a diferenças na resposta a diversos agentes terapêuticos. Com a finalidade de estudar os efeitos de hipolipemiantes e polimorfismos sobre a expressão dos genes HMGCR, LDLR, SREBF1a, SREBF2, SCAP e NPC1L1, foram selecionados 25 indivíduos com hipercolesterolemia familial (HF), 72 com hipercolesterolemia não familial (HNF) e 125 indivíduos normolipidêmicos e sem doença cardiovascular (NL). Os indivíduos HF foram tratados com sinvastatina (40 mg/dia/4 sem) combinada ou não com ezetimiba (10 mg/dia/4sem) e os HNF foram tratados com atorvastatina (10 mg/dia/4sem). Amostras de sangue foram obtidas antes e após o tratamento para a extração de DNA e RNA e analise do perfil lipídico sérico. A expressão de mRNA dos genes SREBF1a, SREBF2, SCAP, HMGCR, LDLR e NPC1L1 em células mononucleares do sangue periférico (CMSP) foi determinada por RT-PCR em tempo real empregando-se o gene da GAPD como controle endógeno. Os polimorfismos SREBF1a 36delG, SREBF2 G1784C e SCAP A2386G foram determinados por PCR-RFLP. Os indivíduos HF apresentaram maior expressão de mRNA dos genes NPC1L1, HMGCR e LDLR que os grupos HNF e NL (p<0,05). O efeito da atorvastatina sobre a expressão dos genes estudados parece depender da expressão basal nos indivíduos HNF. A variação da expressão após o tratamento com atorvastatina nos pacientes do grupo HNF esteve correlacionada nos genes: SREBF1a e SREBF2; SREBF1a e SCAP; SREBF1a e LDLR; SREBF2 e SCAP; SREBF2 e LDLR; HMGCR e LDLR. O tratamento com sinvastatina e ezetimiba não modificou o padrão de expressão dos genes estudados no grupo HF. Os polimorfismos SREBF2 G1784C e SCAP A2386G parecem estar relacionados com diminuição da expressão de mRNA após o tratamento com atorvastatina. Foi observado que os portadores do genótipo GG do polimorfismo SREBF2 G1784C apresentaram maiores concentrações séricas de colesterol total e LDL-C após o tratamento com atorvastatina. O polimorfismo SCAP A2386G parece estar associado com maiores concentrações de apoB em pacientes do grupo HNF antes do tratamento com atorvastatina. Os resultados são sugestivos que os genes HMGCR, LDLR e NPC1L1 são regulados diferentemente de acordo com o estado metabólico do indivíduo e a taxa de expressão de mRNA é influenciada pelos polimorfismos SREBF2 G1784C e SCAP A2386G após o tratamento com atorvastatinaThe regulation of cholesterol is mediated by proteins involved in the absorption (NPC1L1), regulation (SREBP1, SREBP2, SCAP), synthesis (HMGCR) and removal of plasma cholesterol (LDLR). Potent hypocholesterolemic agents inhibit cholesterol synthesis (statins) and its absortion (ezetimibe). Changes in several genes have been associated to different responses to various therapeutic agents. In order to evaluate the association between genes involved in the metabolism of cholesterol and their response to lipid lowering drugs, patients with familial (FH, n = 25) and non familial hypercholesterolemia (NHF, n = 72) were selected. Additionally, 125 normolipidemic individuals and without cardiovascular disease were selected (NL). The HF group were treated with simvastatin (40 mg/day/4 weeks) combined or not with ezetimibe (10 mg/day/4weeks). The NHF group were treated with atorvastatin (10 mg/day/4weeks). Blood samples were obtained prior to and following treatment for extraction of DNA and RNA, and serum lipid profile analysis. The mRNA expression of SREBF1a, SREBF2, SCAP, HMGCR, LDLR, and NPC1L1 genes was determined by real time RT-PCR using the GAPD gene as endogenous control. The polymorphisms SREBF1a-36delG, SREBF2 G1784C, and SCAP A2386G were determined by PCR-RFLP. Individuals with HF showed higher expression of mRNA of genes NPC1L1, HMGCR and LDLR when compared with HNF and NL groups (p <0.05). The effect of atorvastatin on the gene expression seems to depend on the baseline expression in HNF subjects. The change of expression after treatment with atorvastatin in group HNF was correlated as followed: SREBF1a and SREBF2; SREBF1a and SCAP; SREBF1a and LDLR; SREBF2 and SCAP; SREBF2 and LDLR; HMGCR and LDLR. Treatment with simvastatin and ezetimibe did not change the gene-expression profile in HF group. The polymorphisms SREBF2 G1784C, and SCAP A2386G appear to be related to a decreased expression of mRNA after treatment with atorvastatin. HNF group Carriers of GG genotype of SREBF2 G1784C polymorphism had higher serum concentrations of total cholesterol and LDL-C after therapy. The SCAP A2386G polymorphism seems to be associated with higher concentrations of apoB in patients from HNF group prior to treatment with atorvastatin. The results suggest that the HMGCR, LDLR and NPC1L1 genes are regulated according to the metabolic status of the individual, and the expression rate of mRNA is influenced by SREBF2 G1784C and SCAP A2386G polymorphisms after atorvastatin therapy.
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Ohlmann, Anne Katharina [Verfasser]. « Untersuchung von HMGA2 als prognostischer Faktor bei Plattenepithelkarzinomen der Mundschleimhaut insbesondere im Vergleich zu anderen prognostischen Markern / Anne Katharina Ohlmann ». Kiel : Universitätsbibliothek Kiel, 2017. http://d-nb.info/1147380120/34.
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Baier, Jan. « Genetische Faktoren der humanen Cholesterinbiosynthese ». Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-97478.
Texte intégralRésumé :
Background: Genome-wide association studies (GWAs) have identified almost one hundred genetic loci associated with variances in human blood lipid phenotypes including very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol and triglycerides. Nevertheless the revealed loci only explain a small fraction of heritability and therefore a subtile phenotype of cholesterol homoestasis was examined in our study for the very first time.
Methods and Results: Using a multi-stage approach of a GWA, firstly, a genome-wide analysis (Affymetrix 500K GeneChip) for serum lanosterol and serum total cholesterol using LC-MS/MS was conducted in 1495 participants of the KORA-S3/F3 cohort with subsequent replication in two additional independent samples of the the KORA-S3/F3 cohort (n = 1157) and CARLA cohort (n = 1760). Two genetic variants, SNP rs7703051 and rs17562686, in the HMGCR locus were significantly associated with serum lanosterol and showed similar effects of elevated serum lanosterol for each minor allele (combined n = 4412: p = 1,4 x 10-10, +7,1% and p = 4,3 x 10-6, +7,8%). Furthermore, rs7703051 showed a nominal statistical significance to serum cholesterol (p = 0,04). A combined analysis of both SNPs demonstrated that observed associations of rs17562686 can be partly explained by LD with rs7703051 being the primary polymorphism in that study. Nevertheless, rs17562686 shows consistent independent effects on serum lanosterol, thus being associated to a lipid phenotype for the very first time. The following SNP-fine mapping of the HMGCR locus was carried out in the CARLA cohort with subsequent validation in the LE-Heart cohort (n = 1895). The recently published SNP rs3846662 being in tight LD with rs7703051 could be associated with variances of serum lanosterol in both cohorts and functional in vivo studies of gen expression using qRT-PCR assays demonstrated a highly significant association of higher expression of alternatively spliced HMGCR mRNA lacking exon 13 with homozygosity for the rs3846662 major allele in 51 human liver samples (p < 0,01) and 958 human PBMCs (p = 2,1 x 10-7). The overall HMGCR gen expression was not affected. Further investigation of in vivo HMG-CoA reductase enzyme activity in both human samples (n = 48 and n = 55) using anionic exchange column chromatography and scintillation counting of [3-14C]-HMG-CoA and [5-3H]-mevalonolacton did not show any significant results. In addition there was not any association in the LE-Heart cohort between these SNPs and the development of CAD. Finally, rs7703051 could be replicated for already published total cholesterol (combined n = 4412) and rs3846662 for LDL-cholesterol (LE-Heart n = 1895). Since fine mapping in CARLA showed several SNPs throughout the HMGCR locus being in LD with rs17562686 we performed a DNA sequencing of the extended 5´-HMGCR promotor region in six human liver samples. A unknown SNP was discovered in the promotor but could not be associated with any of the examined phenotypes mentioned above. The minor allele of SNP rs5909 situated next to the stop codon and being in high LD with rs17562686 was associated with elevated serum lanosterol and slightly reduced HMGCR gen expression, but further studies including the above mentioned as well as measurement of 3’-UTR transcript lengths using qRT-PCR assays did not produce significant results.
Conclusion: The phenotype serum lanosterol could be associated with genetic polymorphisms (e.g. rs7703051) in the HMGCR locus. Therefore already published associations of HMGCR with total cholesterol and LDL-cholesterol can be explained by variances of cholesterol homeostasis. The SNP rs17562686 could be associated with a phenotype of human blood lipids for the very first time. Subsequent gen expression analyses demonstrated a highly significant association of rs3846662 with variant patterns of HMGCR alternative splicing. A significant effect of alternatively spliced protein on enzyme activity and a association of these SNPs with CAD could not be shown.
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Winston, Eugenia Michele. « The Utilization of the Hmg2 Inducible Promoter to Genetically Engineer Parasite Resistance in Tobacco ». Diss., Virginia Tech, 2003. http://hdl.handle.net/10919/27200.
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The cyst nematode, Globodera tabacum tabacum Behrens, and the parasitic angiosperm, Egyptian broomrape, Orobanche aegyptiaca Pers., are obligate root parasites that cause severe yield and quality loss of many important crop hosts. Although these represent two diverse classes of parasites, they have significant similarities in the modes of parasitism and complex interactions with their hosts. Conventional control methods have had limited success in controlling these parasites. The overall objective of this research was to engineer resistance to the cyst nematode and Egyptian broomrape by expressing genes encoding parasite specific toxins under the control of parasite-responsive promoters using tobacco (Nicotiana tabacum L. cv. Xanthi). For nematode resistance, an anti-feeding strategy was employed utilizing the tomato proteinase inhibitor I (PI-I) gene as a nematode specific toxin. Transgenic tobacco plants were generated that expressed genes encoding an intracellarly retained or secreted form of tomato PI-I under the control of the nematode-inducible promoter, derived from tomato (Lycopersicon esculentum L.) Hmg2 gene. Our goals were to determine the effectiveness of local PI-I expression on nematode resistance and to determine if intracellular or extracellular PI-I deposition enhances resistance. Two constructs were generated that contained either the coding region of the tomato PI-I gene, lacking the signal sequence (EM1), or the coding region of PI-I including the signal sequence (EM2), fused to the nematode-responsive Hmg2 promoter. Transgenic PI-I plants were inoculated with G. t. tabacum cysts and evaluated for nematode interactions. Our results suggest that local expression of intercellular of PI-I significantly reduced cyst production when compared to the nontransformed controls. For broomrape resistance, a well characterized R/avr gene pair, the tobacco N resistance gene and the tobacco mosaic virus replicase (TMV) gene, was utilized to create novel gene-for-gene resistance via a N gene-mediated hypersensitive response (HR) to limit broomrape parasitism. The bean (Phaselous vulgaris L.) chalcone synthase 8 (CHS8) promoter has been characterized as a broomrapeâ responsive promoter. We introduced the CHS8:TMV replicase gene construct into tobacco plants that contains an endogenous N gene. Transgenic tobacco plants were inoculated with O. aegyptiaca seeds and monitored for parasite attachment and development. The expression of the TMV replicase leads to a significant reduction in broomrape parasitism. These genetic engineering strategies show promise in enhancing resistance to these destructive parasites.Ph. D.
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Sousa, Stanley Silvano. « ANÁLISE DO POLIMORFISMO NA REGIÃO PROMOTORA -911 NO GENE DA 3-HIDROXIMETILGLUTARIL-COA REDUTASE (HMGCR) EM PACIENTES COM DOENÇA ARTERIAL CORONARIANA ». Pontifícia Universidade Católica de Goiás, 2015. http://localhost:8080/tede/handle/tede/2400.
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Previous issue date: 2015-08-27The main regulatory enzyme of cholesterol biosynthesis is hydroxyl-methylglutaryl-CoA reductase (HMGCR) and several polymorphisms are described in the gene encoding this enzyme. Currently, associations between genetic polymorphisms and cardiovascular disease are investigated in order to better understand the genetic factors associated with such diseases. The objective of this study was to evaluate the frequency of -911 polymorphism (rs3761740) in the promoter region of HMGCR gene in patients with coronary artery disease (CAD), as well as the possible associations between the resultant genotypes and clinical features of patients with CAD. Genomic DNA isolated from patients blood samples were analyzed for the detection of genetic polymorphism, by using polymerase chain reaction (PCR) analysis and restriction fragment length polymorphism (RFLP). Allele frequencies obtained for the -911 polymorphism (rs3761740) in the promoter region of the HMGCR gene were: A (51.2%) and C (48.8%). The genotype frequencies obtained were: AA (11.9%), AC (78.6%) and CC (9.5%). Significant associations between the diferente genotypes and clinical features of the patients with CAD were not detected in this study. Our results show that -911 polymorphism (rs3761740) in the promoter region of the HMGCR gene was not associated with clinical and laboratory characteristics in patients with coronary artery disease.
A principal enzima regulatória da biossíntese do colesterol é a hidrox-imetilglutaril-CoA redutase (HMGCR) e vários polimorfismos são descritos no gene que codifica esta enzima. Atualmente, associações entre tais polimorfismos genéticos e as doenças cardiovasculares são investigadas no sentido de compreender melhor os fatores genéticos associados a essas doenças. O objetivo deste estudo foi avaliar a frequência do polimorfismo -911(rs3761740) na região promotora do gene da HMGCR em pacientes com doença arterial coronariana (DAC), bem como as possíveis associações entre os genótipos encontrados e os aspectos clínicos dos pacientes com DAC. O DNA genômico isolado das amostras de sangue dos pacientes foi analisado para detecção do polimorfismo genético, por meio da reação em cadeia da polimerase (PCR) e análise de polimorfismos de comprimento de fragmentos de restrição (RFLP). As frequências alélicas obtidas para o polimorfismo -911 (rs3761740) na região promotora do gene HMGCR foram: A (51,2%) e C (48,8%). As frequências genotípicas obtidas foram: AA (11,9%), AC (78,6%) e CC (9,5%). Associações significativas entre os genótipos encontrados e os aspectos clínicos dos pacientes com DAC não foram detectadas neste estudo. Nossos resultados permitem concluir que polimorfismo -911(rs3761740) na região promotora do gene da HMGCR não esteve associado aos aspectos clínicos e laboratoriais em pacientes com doença arterial coronariana.
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Kil, Eric Joon Bum. « CRISPR-Cas9 mediated HMGCL KO in 3xTg AD mice reduces the cognitive deficit improvement seen in an intermittent metabolic switching regimen ». Scholarship @ Claremont, 2018. http://scholarship.claremont.edu/cmc_theses/1832.
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Individuals in modern Western societies are experiencing increasing sedentary lifestyles, overindulgence of high fat, high-sugar diets, and extremely sterilized conditions, putting immense pressure on researchers and clinicians alike to come up with viable treatments for conditions implicated with an aging society. Emerging research have published the benefits of IMS and metabolic switching in a variety of neuroprotective, cellular stress resistance, and neuroplasticity pathways in animal models and clinical results from randomized trials of IMS regimens with susceptible human populations are soon to be published. The application of genome editing and next-generation sequencing (NGS) strategies to clinical and neurodegenerative research continues to elucidate the relationship between a patient’s specific genetic background and modern environmental stressors towards disease pathology. This study attempts to utilize novel CRISPR/Cas9 strategies to introduce targeted gene edits and explores the role of reduced ketone-body synthesis/metabolism with 3-hydroxymethyl-3-methylglutaryl-CoA lyase HMGCL KO, in the therapeutic and neuroprotective potential of intermittent metabolic switching in 3xTg mice, genetically predisposed for Alzheimer pathology. IMS-mediated attenuation of hippocampal spatial memory deficits was confirmed in 5-month-old 3xTg mice using Morris Water Maze and Aβ1-40, Aβ1-42, total tau and p-tau levels were calculated accordingly. Mice receiving time-restricted feeding (TRF) and caloric restriction (CR) regardless of KO performed better in the hippocampal-dependent spatial memory test and ELISA analysis of CSF revealed reduced p-tau levels of 3xTg WT TRF + CR mice relative to WT control or the two experimental groups. Overall, genetic modifications of key metabolic enzymes highlight the variable therapeutic results of the glucose to ketone metabolic switch on cognitive deficits depending on an organism’s genetic background.
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Aguiar, Tamiris Sayuri. « Caracterização de variação no número de cópias (CNV) no gene HMGA2 associado com tamanho de prepúcio em bovinos nelore (Bos indicus) / ». Jaboticabal, 2018. http://hdl.handle.net/11449/154763.
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Orientador: José Fernando GarciaBanca: Silvana de Cássia Paulan
Banca: Flávia Lombardi Lopes
Resumo: O gene High Mobility Group AT-hook2 (HMGA2) apresentou fortes evidências de estar associado com o tamanho de umbigo em bovinos da raça Nelore através da análises de associação genômica ampla (GWAS). Diversos relatos de associação desse gene a fenótipos do âmbito da morfologia corporal existem para diferentes espécies, tais como altura em humanos, cães e equinos, e tamanho da orelha em suínos. Descobertas recentes demonstraram que o gene HMGA2 está associado avia metabólica de grande importância fisiológica e biológica que tem como um dos principais fatores o PLAG1 (Pleomorphic adenoma gene1), que está associado ao fator de crescimento semelhante à insulina 2 (IGF2), importante regulador do crescimento e da reprodução em bovinos. No presente trabalho, foi descritaa identificação e caracterização de variação no número de cópias (CNV) cromossomo 5 do cromossomo bovino, na região do gene HMGA2 que apresenta associação a característica de tamanho de umbigo. Análises da sequência completa do genoma de indivíduos Bos taurus e Bos indicus foram empregadas para caracterizar o CNV, sendo sua validação realizada através de PCR quantitativo (qPCR). Além disso, os resultados foram comparados com dados de sequência de animais africanos B. indicus evidenciando a origem zebuína do CNV.
Abstract: The High Mobility Group AT-hook 2 (HMGA2) gene presented strong evidence of being associated with navel size in Nellore cattle through genome association analysis (GWAS). Several reports of association of this gene with phenotypes in the scope of body morphology exist for different species, such as height in humans, dogs and horses, and ear size in swine. Recent discoveries have shown that the HMGA2 gene is associated with a metabolic pathway of great physiological and biological importance that has as one of its main factors PLAG1 (Pleomorphic adenoma gene 1), which is associated with insulin-like growth factor 2 (IGF2), important regulator of growth and reproduction in cattle. In the present work, the identification and characterization of copy number variation (CNV) on chromosome 5 of the bovine chromosome in the region of the HMGA2 gene that has association with the navel size trait was described. Genome sequence analysis of Bos taurus and Bos indicus individuals was used to characterize the CNV, and its validation was performed using quantitative PCR (qPCR). In addition, the results were compared with sequence data from a African B.indicus animals evidencing the indicine origin of the CNV.
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Boquel, Pascal. « Synthèse énantiospécifique d'acides méviniques : une nouvelle approche ». Nancy 1, 1989. http://www.theses.fr/1989NAN10528.
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La synthèse énantiospécifique de divers analogues à la compactine, inhibiteur de HMGCoA réductase, a été entreprise. L'accès facile et rapide à des composés de structures didésoxy - 2 - 4 - hexopyrannose, chirons clefs dans ce type de synthèse, a été réalisée par transformation stéréospécifique du glucose et du mannose. L'élaboration d'une méthode de création de liaison carbone-carbone qui revient à allonger la chaîne d'un dérivé sucré en C-6, tout en permettant la désoxygènation simultanée en C-4 a été mise au point. Les travaux sur une nouvelle classe d'inhibiteurs de HMGCoA réductase incorporant un reste pyridinique en applicant aux glucides une réaction originale ont été poursuivis. Lors de cette réaction un phénomène d'épimérisation a été remarqué, son origine et le moyen de l'éviter ont fait l'objet d'une étude approfondie
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Mello, Julia Bette Homem de [UNESP]. « Caracterização de mutações no gene MED12, dos miRNAS mapeados em 7q22 e dos candidatos a regulação do gene HMGA2 em leiomiomas uterinos ». Universidade Estadual Paulista (UNESP), 2013. http://hdl.handle.net/11449/92717.
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mello_jbh_me_botib.pdf: 2352640 bytes, checksum: f06cfab104960439db36f6c6549acc56 (MD5)Leiomiomas uterinos (LU) são tumores benignos de origem mesenquimal frequentes sendo considerados um problema de saúde pública. A desregulação de fatores de crescimento e microRNAs, encurtamento dos telomeros, produção excessiva e desorganizada de matriz extracelular, perda de heterozigose e alterações cromossômicas recorrentes (como deleção em 7q22 e rearranjo cromossômico em 12q15) contribuem para o crescimento dos LU. Uma parcela significativa destes tumores apresenta mutação no gene MEDI2. O presente estudo teve como objetivo avaliar: a presença da mutação no MEDI2; o nível de expressão do HMGA2 e seus miRNAs preditos (let-7a, miR-26a, miR-26b); o nível de expressão do, cluster de miRNAs mapeado em 7q22 (miR-25, miR-93 e miR- 106b) e a expressão dos genes BRCAI, FANCA e seus miRNAs preditos. Foram avaliados 85 LU e 34 amostras de miométrio adjacentes obtidos de 54 pacientes submetidos à histerectomia. A análise de expressão por RT-qPCR foi realizada para os miR-let7a, miR-25, miR-93, miR-106b, miR-21, miR-26a, miR-26b, miR-197 e miR- 143, utilizando RNU44 , RNU48 e U47 como endógenos. Foi também avaliada a expressão dos genes HMGA2, BRCAI e FANCA sendo utilizados como controles endógenos RPLPO e GUSB. A mutação no MED12 foi encontrada em 50% (42/85) das amostras. Foi observado um aumento significativo (p<0,001) dos níveis de expressão do HMGA2 nos LU comparados ao miométrio adjacente, inclusive nas amostras com presença da mutação em MEDI2. Estes dados sugerem que o aumento de expressão do HMGA2 e a mutação em MEDI2 podem coexistir nestes tumores. Os miRNAs preditos para regular o HMGA2 apresentaram diminuição dos níveis de expressão: let-7a (p
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Busch, Bianca [Verfasser], Stefan [Akademischer Betreuer] Hüttelmaier, Guido [Akademischer Betreuer] Posern et Gunter [Akademischer Betreuer] Meister. « Charakterisierung des miR-let-7-abhängigen onkogenen Netzwerks von IGF2BP1-LIN28B-HMGA2 in Ovarialkarzinomzellen / Bianca Busch ; Stefan Hüttelmaier, Guido Posern, Gunter Meister ». Halle, 2016. http://d-nb.info/1116952165/34.
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Mello, Julia Bette Homem de. « Caracterização de mutações no gene MED12, dos miRNAS mapeados em 7q22 e dos candidatos a regulação do gene HMGA2 em leiomiomas uterinos / ». Botucatu, 2013. http://hdl.handle.net/11449/92717.
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Orientador: Silvia Regina RogattoBanca: Rafael Malagoli Rocha
Banca: Robson Francisco Carvalho
Resumo: Leiomiomas uterinos (LU) são tumores benignos de origem mesenquimal frequentes sendo considerados um problema de saúde pública. A desregulação de fatores de crescimento e microRNAs, encurtamento dos telomeros, produção excessiva e desorganizada de matriz extracelular, perda de heterozigose e alterações cromossômicas recorrentes (como deleção em 7q22 e rearranjo cromossômico em 12q15) contribuem para o crescimento dos LU. Uma parcela significativa destes tumores apresenta mutação no gene MEDI2. O presente estudo teve como objetivo avaliar: a presença da mutação no MEDI2; o nível de expressão do HMGA2 e seus miRNAs preditos (let-7a, miR-26a, miR-26b); o nível de expressão do, cluster de miRNAs mapeado em 7q22 (miR-25, miR-93 e miR- 106b) e a expressão dos genes BRCAI, FANCA e seus miRNAs preditos. Foram avaliados 85 LU e 34 amostras de miométrio adjacentes obtidos de 54 pacientes submetidos à histerectomia. A análise de expressão por RT-qPCR foi realizada para os miR-let7a, miR-25, miR-93, miR-106b, miR-21, miR-26a, miR-26b, miR-197 e miR- 143, utilizando RNU44 , RNU48 e U47 como endógenos. Foi também avaliada a expressão dos genes HMGA2, BRCAI e FANCA sendo utilizados como controles endógenos RPLPO e GUSB. A mutação no MED12 foi encontrada em 50% (42/85) das amostras. Foi observado um aumento significativo (p<0,001) dos níveis de expressão do HMGA2 nos LU comparados ao miométrio adjacente, inclusive nas amostras com presença da mutação em MEDI2. Estes dados sugerem que o aumento de expressão do HMGA2 e a mutação em MEDI2 podem coexistir nestes tumores. Os miRNAs preditos para regular o HMGA2 apresentaram diminuição dos níveis de expressão: let-7a (p
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Cano, Corres Ruth. « Influencia de variantes de los genes APOE, HMGCR, SLC01B1, CYP3A4 y LPA en la respuesta al tratamiento con estatinas en pacientes con dislipemia ». Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/286273.
Texte intégralRésumé :
Los pacientes con dislipemia son tratados con estatinas para reducir sus concentraciones de lípidos, y disminuir el riesgo cardiovascular. El grado de respuesta a estos fármacos es heterogéneo, y en él podrían influir ciertos genes. Este trabajo trata de valorar la influencia de seis variantes genéticas sobre la eficacia de las estatinas en pacientes con dislipemia, tanto de manera independiente como junto a una serie de variables de control. Las magnitudes lipídicas evaluadas fueron el colesterol total (CT) y el excluido de HDL (noHDL), y las variables de control fueron: edad, dosis media diaria de estatina, cambio en el índice de masa corporal, cambio en el hábito tabáquico, cambio en las horas de ejercicio practicadas semanalmente y cambio en el consumo de gramos de alcohol diarios. La eficacia del tratamiento se valoró mediante tres indicadores: disminución relativa de CT y no HDL según la concentración al final (%C) y según la concentración media durante el tratamiento (%CM), y grado de consecución de objetivos terapéuticos. Este estudio se llevó a cabo en una población NAIF (n=100), pacientes en los que se inicia el tratamiento en la primera visita, y posteriormente en una población NO NAIF (n=57), pacientes ya tratados en la primera visita a quienes se les modifica el tratamiento. Las variantes genéticas estudiadas fueron: APOE c.526C>T (APOE2), APOE c.388T>C (APOE4), SLCO1B1 c.521T>C, CYP3A4 c.-392G>A, HMGCR c.1564-106A>G y LPA c.3947+467T>C. El estudio estadístico se basó en modelos de regresión múltiple. Para la población NAIF, la variante HMGCR c.1564-106A>G resultó influir sobre el %C y el %CM tanto para CT como para noHDL. Aportó al modelo basal un porcentaje de explicación adicional para %C de CT y noHDL de un 9,5% y 8,2%, respectivamente, y 6,2% y 3,5% al del %CM. También resultó influyente para los NO NAIF, suponiendo una explicación adicional de aproximadamente un 8% para los cuatro casos. Cabe destacar que en ambas poblaciones el efecto de la presencia de la variante resultó contrario: perjudicial para los NAIF y beneficioso para los NO NAIF. El gen HMGCR codifica para la enzima sobre la que ejercen su acción las estatinas. La variante estudiada está implicada en la regulación del splicing alternativo del exón 13, que modifica los centros activos sobre los que puede actuar la estatina. Este splicing alternativo también se ve modulado por la concentración de lípidos circulantes, pero esto ocurre únicamente en los no portadores de la variante. En esta tesis se postula que la disminución del CT y el noHDL se producirían de manera gradual y constante en el caso de los portadores de la variante, o según una función de tipo sigmoideo en los no portadores. Además, para los NO NAIF, la variante SLCO1B1 c.521T>C resultó influyente y perjudicial para el %C y %CM del CT, aportando un 7,1% y 5,9% de explicación al modelo basal respectivamente. Esto podría deberse a la relación entre la variante y los efectos adversos de las estatinas, que suele llevar aparejada una mala adhesión al tratamiento. Respecto al grado de consecución de los objetivos terapéuticos, las variantes influyentes fueron HMGCR c.1564-106A>G para el CT para los NAIF, y SLCO1B1 c.521T>C para CT y noHDL de los NO NAIF. La presencia de las variantes supuso mayor dificultad para alcanzar los objetivos. Se puede concluir que la variante estudiada del gen HMGCR tiene cierta influencia sobre la eficacia de las estatinas, aunque su efecto depende del tipo de población estudiada. La presencia de la variante del gen SLCO1B1 también podría presentar cierto efecto perjudicial, pero en ambos casos sería recomendable ampliar el estudio con un mayor número de pacientes.Patients with dislipemia are often treated with statins to reduce lipids and cardiovascular risk. It is known that the efficacy of statins is variable between patients, so a genetic influence is suspected. This work tries to assess the influence of six genetic variants on the efficacy of statins employing three indicators: percentage reduction of total cholesterol (CT) and noHDL cholesterol (noHDL) according to final concentration (%C) and to mean concentration (%CM), as well as achievement of therapeutic objectives. The study was first developed in a population of patients who were not treated at the first visit (NAIF) and then it was repeated with patients treated in the first visit whose treatment was changed (NO NAIF). The genetic variants were: APOE c.526C>T (APOE2), APOE c.388T>C (APOE4), SLCO1B1 c.521T>C, CYP3A4 c.-392G>A, HMGCR c.1564-106A>G y LPA c.3947+467T>C. The statistical analysis employs multiple regression models to define the percentage of explanation added by the variant to a basal model constructed with the significant control variables. The most influential variant was HMGCR c.1564-106A>G which added an explanation of 9,5%, 8,5%, 6,2% and 3,5% to the indicators %C CT and noHDL, and %CM CT and noHDL in NAIF population. For NO NAIF it added an explanation of over 8% in the same cases. The presence of the variant showed an opposite effect in both populations: harmful for NAIF and beneficial for NO NAIF. This variant is related to an alternative splicing of the exon 13, which is also regulated by lipids concentrations, but only in patients without the variant. This work postulates that the reduction of CT and noHDL is gradual for variant carriers, but follows a sigmoid function for non-carriers. For NO NAIF the SLCO1B1 c.521T>C variant was harmful for %C and %CM of CT, adding explanations of 7,1% and 5,9%. This could be due to the relationship between this variant and the adverse effects of statins, which usually means worse treatment adherence. About therapeutic objectives, the variant HMGCR c.1564-106A>G was influent for CT of NAIF and SLCO1B1 c.521T>C for CT and noHDL of NO NAIF, hindering the achievement of therapeutic objectives in both cases.
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Winter, Nina [Verfasser], Jörn [Akademischer Betreuer] Bullerdiek et Burkhard [Akademischer Betreuer] Helmke. « Nachweis der Expression von HMGB1 und HMGA2 zur Anwendung in der Tumor- und Pränataldiagnostik / Nina Winter. Gutachter : Jörn Bullerdiek ; Burkhard Helmke. Betreuer : Jörn Bullerdiek ». Bremen : Staats- und Universitätsbibliothek Bremen, 2012. http://d-nb.info/1071993445/34.
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Lepko, Tjaša [Verfasser], et Jovica [Akademischer Betreuer] Ninkovic. « The role of chromatin associated protein HMGB2 in setting up permissive chromatin states for direct glia to neuron conversion / Tjaša Lepko ; Betreuer : Jovica Ninkovic ». München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1171131380/34.
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Thies, Helge Wilhelm [Verfasser], Jörn [Akademischer Betreuer] Bullerdiek et Andreas [Akademischer Betreuer] Dotzauer. « Untersuchung zur Rolle von HMGA2 im Fettgewebe : Mechanismen des Turnovers und der Hyperplasie / Helge Wilhelm Thies. Gutachter : Jörn Bullerdiek ; Andreas Dotzauer. Betreuer : Jörn Bullerdiek ». Bremen : Staats- und Universitätsbibliothek Bremen, 2014. http://d-nb.info/107215840X/34.
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Ronfani, Lorenza. « Cloning and knock-out of the mouse gene coding for the high mobility group 2 protein (HMG2) ». Thesis, Open University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342940.
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Müller, Marietta Henrike [Verfasser], Jörn [Akademischer Betreuer] Bullerdiek et Andreas [Akademischer Betreuer] Dotzauer. « Dysregulation of the high mobility group AT-hook 2 (HMGA2) gene in human tumours / Marietta Henrike Müller. Gutachter : Jörn Bullerdiek ; Andreas Dotzauer. Betreuer : Jörn Bullerdiek ». Bremen : Staats- und Universitätsbibliothek Bremen, 2014. http://d-nb.info/1072226219/34.
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Hronskiy, Oleksiy. « Grazing Legacy Influence Nutrient Content and Dry Matter Digestibility of Five Reindeer Food Plants ». Thesis, Umeå universitet, Institutionen för ekologi, miljö och geovetenskap, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-174776.
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Herbivores have a significant role in tundra ecosystem composition and processes. They can cause changes of vegetation composition and nutrient content that result in altered palatability of the vegetation and food availability for herbivores. The direct effect of herbivores on plant quality and quantity have been studied in detail, and recent studies have shown that present vegetation composition and soil processes might show legacies of historical grazing a century ago. This raises the question if historical grazing also has a legacy on the palatability of the vegetation. In this study, I investigated if the quality of the vegetation of the Historical Milking Grounds (HMGs) heavily grazed up until a century ago is still under influence a century after the heavy grazing has ceased. I focused on the nitrogen content and digestibility of the vegetation, since these should be two independent measures of food quality which, when evaluated together, should give a good estimate of the quality of the forage.
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Sobajima, Junko. « 新規のP-ANCA対応抗原HMG1/HMG2の同定と抗HMG1/HMG2抗体の潰瘍性大腸炎および自己免疫性肝炎における臨床的意義の研究 ». Kyoto University, 2000. http://hdl.handle.net/2433/151440.
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Caron, Leslie. « Rôle de la voie ERK et du facteur de transcripion HMGA2 dans la différenciation des cellules souches embryonnaires de souris : établissement du système d'expression inductible Lacl-IPTG dans ces cellules ». Nice, 2004. http://www.theses.fr/2004NICE4068.
Texte intégralRésumé :
Nous avons étudié le rôle du facteur de transcription HMGA2, dans la différenciation ces cellules souches embryonnaires de souris (ES). Des cellules ES surexprimant la forme tronquée (HMGA2/T) ou entière (HMGA2wt) de HMGA2 ont été établies et analysées pour leur capacité à se différencier dans divers lignages. Contrairement aux cellules sauvages ou surexprimant HMGA2wt, les cellules ES HMGA2/T développent des myotubes contractiles. Les tératocarcinomes induits par les cellules ES HMGA2/T forment de larges zones de tissu musculaire squelettique, jamais observées dans les tumeurs issues des cellules contrôles. En revanche, la surexpression de HMGA2 n'affecte pas l'engagement des cellules ES dans les autres lignages. Ces résultats montrent un nouveau rôle de HMGA2 dans la différenciation du muscle squelettique. La seconde partie concerne l'établissement du système d'expression inductible LacI/IPTG dans les cellules ES. En absence d'inducteur, le répresseur LacI réprime la transcription du gène d'intérêt en se fixant sur des séquences opératrices. La répression est levée par l'IPTG. Deux séquences opératrices ont été insérées au sein du promoteur de la b-actine et permettent une régulation efficace du transgène, dans les cellules ES exprimant LacI. Des cellules ES exprimant la GFP sous contrôle du promoteur inductible ont été établies. L'induction de la GFP par l'IPTG est maintenue tout au long du processus de différenciation et a pu être observée dans les cardiomyocytes et les neurones dérivés des cellules ES. Ce système d'expression inductible pourra maintenant être utilisé pour déterminer précisément le rôle du facteur de transcription HMGA2 dans la différenciationWe investigated the role of the HMGA2 transcription factor during mouse embryonic stem cells differentiation (ES cells). ES cells overexpressing either wild-type (HMGA2wt) or truncated (HMGA2/T) form of HMGA2 were analysed for their capacities to differentiate into a variety of lineage. Following differentiation, as opposed to control cells and HMGA2wt ES cells, overexpressing HMGA2/T ES cells massively formed contractile myotubes and highly expressed the muscle Myosin Heavy Chain marker. Interestingly, in experimental conditions inhibitory for myogenesis, we observed a strong expression of MyoD and myogenin in HMGA2/T cells. By contrast, commitment into adipocyte, neuron and cadiomyocyte lineages was not affected. Finally, teratocarcinomas induced by HMGA2/T ES cell lines presented numerous skeletal muscle-differentiated tissues that were not observed in wt HMGA2 or control tumors. Our results reveal a novel function of the oncogenic form of HMGA2 in skeletal muscle differentiation. Control of mammalian gene promoters by the bacterial LacI repressor provides inducible regulation and dose-response levels of expression by the lactose analog IPTG. We show that insertion of LacI binding sites in the b-actin promoter confers an efficient IPTG-regulatable expression of reporter genes in ES cells expressing LacI. We established ES cell lines stably expressing GFP under inducible control and found that this regulatable expression was maintained throughout the differentiation process. Importantly, GFP induction by IPTG was observed in individual well-differentiated cardiomyocytes and neurons. This inducible system will be used to study HMGA2 during ES cells differentiation