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1
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.
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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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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.
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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
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.
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The high-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor highly expressed in fetal tissue and malignant tumors but rarely detected within normal adult tissues. The clinical implications and biological functions of HMGA2 in endometrial carcinoma are largely unknown. Here we report that HMGA2 expression was barely detected in benign endometrium samples (2 of 28 samples). However, HMGA2 expression increased significantly from precancerous lesion endometrial glandular dysplasia (7 of 17, 41.2%), to serous endometrial intraepithelial carcinoma (5 of 8, 62.5%) and to full blown endometrial serous carcinoma (39 of 59, 66.1%). Functional characterization of HMGA2 revealed that the gene has both tumor growth promotion and metastasis. In addition, HMGA2 induced epithelial-mesenchymal transition (EMT) through modulation vimentin and β-catenin. Furthermore, HMGA2 overexpression started from endometrial serous precancers, non-invasive cancers, as well as in full blown carcinomas in a p53 knockout mouse model we recently established in our laboratory. Our findings suggest that HMGA2 may serve as a useful diagnostic marker in the assessment of endometrial serous cancer and its precursor lesions.
4
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.
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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.
5
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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Natarajan, Suchitra. "Roles of high mobility group AT-hook protein 2 (HMGA2) in human cancers." Elsevier, 2013. http://hdl.handle.net/1993/31092.
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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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Saada-Bouzid, Esma. "Étude génomique et fonctionnelle de la dérégulation du gène HMGA2 dans les tumeurs adipocytaires." Electronic Thesis or Diss., Nice, 2015. http://www.theses.fr/2015NICE4000.
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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
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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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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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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.
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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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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.
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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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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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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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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.
Mestre
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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, and 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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Winter, Nina [Verfasser], Jörn [Akademischer Betreuer] Bullerdiek, and 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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Thies, Helge Wilhelm [Verfasser], Jörn [Akademischer Betreuer] Bullerdiek, and 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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Müller, Marietta Henrike [Verfasser], Jörn [Akademischer Betreuer] Bullerdiek, and 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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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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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.
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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
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Sneesby, Kyra, and n/a. "Gene Expression in Embryonic Chick Heart Development." Griffith University. School of Biomolecular and Biomedical Science, 2003. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20030924.153514.
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Establishment of the biochemical and molecular nature of cardiac development is essential for us to understand the relationship between genetic and morphological aspects of heart formation. The molecular mechanisms that underly heart development are still not clearly defined. To address this issue we have used two approaches to identify genes involved in early chick cardiac development. Differential display previously conducted in our laboratory led to the identification of two gene fragments differentially expressed in the heart that are further described in this thesis. The full-length cDNA sequence of both eukaryotic translation initiation factor-2b (eIF-2b) and NADH cytochrome b5 reductase (b5R) were isolated using library screening. The upreglation of these genes during heart development is expected given the heart is the first functional organ to form in vertebrates and protein synthesis and cell metabolism at this stage of development is maximal. Limitations in the differential display approach led to the development and optimisation of a subtractive hybridisation approach for use with small amounts of cells or tissue. To focus on cardiac gene expression during the initial phases of heart development, subtractive hybridization was performed between the cardiogenic lateral plate mesoderm of Hamburger and Hamilton stage 4 embryos and the heart primordia of stage 9 embryos. Of the 87 independent clones identified by this procedure, 59 matched known sequences with high homology, 25 matched unknown expressed sequence tag (EST) sequences with high homology, and 3 did not match any known sequence on the database. Known genes isolated included those involved in transcription, translation, cell signalling, RNA processing, and energy production. Two of these genes, high mobility group phosphoprotein A2 (HMGA2) and C1-20C, an unknown gene, were chosen for further characterisation. The role of each gene in early chick heart development and indeed development in general, was addressed using techniques such as in situ hybridisation, transfection analysis, in ovo electroporation and RNAi. HMGA2 is a nuclear phosphoprotein commonly referred to as an architectural transcription factor due to its ability to modulate DNA conformation. In keeping with this function, HMGA2/GFP fusion protein was shown to localise to the nucleus and in particular, the nucleolus. In situ hybridisation analysis suggested a role for HMGA2 in heart and somite development. HMGA2 expression was first detected at HH stage 5 in the lateral plate mesoderm, a region synonymous with cells specified to the cardiac fate. HMGA2 was also strongly expressed in the presomitic segmental plate mesoderm and as somites developed from the segmental plate mesoderm, the expression of HMGA2 showed an increasingly more restricted domain corresponding to the level of maturation of the somite. Restriction of HMGA2 expression was first detected in the dorsal region of the epithelial somite, then the dorsomedial lip of the dermomyotome, and finally the migrating epaxial myotome cells. The novel intronless gene, C1-20C, predicts a protein of 148 amino acids containing a putative zinc finger binding domain and prenyl binding motif. Zinc binding assays showed that the zinc finger domain of C1-20C/MBP fusion protein bound over six times the quantity of zinc compared to MBP alone, although not in a 1:1 stoichiometric molar ratio. C1-20C/GFP fusion protein was shown to localise to as yet unidentified intracellular cytoplasmic vesicular compartments. These compartments did not colocalise with the endosome/lysosome pathway, aparently ruling out a role for C1-20C in protein trafficking, recycling or degradation. Expression of C1-20C in the chick embryo suggests a possible role in heart and notochord development and preliminary results using siRNA suggest that C1-20C is involved in normal heart looping.
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Sneesby, Kyra. "Gene Expression in Embryonic Chick Heart Development." Thesis, Griffith University, 2003. http://hdl.handle.net/10072/367647.
Full textAbstract:
Establishment of the biochemical and molecular nature of cardiac development is essential for us to understand the relationship between genetic and morphological aspects of heart formation. The molecular mechanisms that underly heart development are still not clearly defined. To address this issue we have used two approaches to identify genes involved in early chick cardiac development. Differential display previously conducted in our laboratory led to the identification of two gene fragments differentially expressed in the heart that are further described in this thesis. The full-length cDNA sequence of both eukaryotic translation initiation factor-2b (eIF-2b) and NADH cytochrome b5 reductase (b5R) were isolated using library screening. The upreglation of these genes during heart development is expected given the heart is the first functional organ to form in vertebrates and protein synthesis and cell metabolism at this stage of development is maximal. Limitations in the differential display approach led to the development and optimisation of a subtractive hybridisation approach for use with small amounts of cells or tissue. To focus on cardiac gene expression during the initial phases of heart development, subtractive hybridization was performed between the cardiogenic lateral plate mesoderm of Hamburger and Hamilton stage 4 embryos and the heart primordia of stage 9 embryos. Of the 87 independent clones identified by this procedure, 59 matched known sequences with high homology, 25 matched unknown expressed sequence tag (EST) sequences with high homology, and 3 did not match any known sequence on the database. Known genes isolated included those involved in transcription, translation, cell signalling, RNA processing, and energy production. Two of these genes, high mobility group phosphoprotein A2 (HMGA2) and C1-20C, an unknown gene, were chosen for further characterisation. The role of each gene in early chick heart development and indeed development in general, was addressed using techniques such as in situ hybridisation, transfection analysis, in ovo electroporation and RNAi.
HMGA2 is a nuclear phosphoprotein commonly referred to as an architectural transcription factor due to its ability to modulate DNA conformation. In keeping with this function, HMGA2/GFP fusion protein was shown to localise to the nucleus and in particular, the nucleolus. In situ hybridisation analysis suggested a role for HMGA2 in heart and somite development. HMGA2 expression was first detected at HH stage 5 in the lateral plate mesoderm, a region synonymous with cells specified to the cardiac fate. HMGA2 was also strongly expressed in the presomitic segmental plate mesoderm and as somites developed from the segmental plate mesoderm, the expression of HMGA2 showed an increasingly more restricted domain corresponding to the level of maturation of the somite. Restriction of HMGA2 expression was first detected in the dorsal region of the epithelial somite, then the dorsomedial lip of the dermomyotome, and finally the migrating epaxial myotome cells. The novel intronless gene, C1-20C, predicts a protein of 148 amino acids containing a putative zinc finger binding domain and prenyl binding motif. Zinc binding assays showed that the zinc finger domain of C1-20C/MBP fusion protein bound over six times the quantity of zinc compared to MBP alone, although not in a 1:1 stoichiometric molar ratio. C1-20C/GFP fusion protein was shown to localise to as yet unidentified intracellular cytoplasmic vesicular compartments. These compartments did not colocalise with the endosome/lysosome pathway, aparently ruling out a role for C1-20C in protein trafficking, recycling or degradation. Expression of C1-20C in the chick embryo suggests a possible role in heart and notochord development and preliminary results using siRNA suggest that C1-20C is involved in normal heart looping.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
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Kloth, Lars-Gerrit [Verfasser], Jörn [Akademischer Betreuer] Bullerdiek, and Andreas [Akademischer Betreuer] Dotzauer. "Quantitative analysis of thyroid adenoma associated (THADA) and high-mobility group AT-hook 2 (HMGA2) in dedifferentiated and extra-embryonic human tissues / Lars-Gerrit Kloth. Betreuer: Jörn Bullerdiek. Gutachter: Jörn Bullerdiek ; Andreas Dotzauer." Bremen : Staats- und Universitätsbibliothek Bremen, 2015. http://d-nb.info/1077864280/34.
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Lamichhaney, Sangeet. "The genetic basis for adaptation in natural populations." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-279969.
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Many previous studies in evolutionary genetics have been based on few model organisms that can be reared at ease in the laboratory. In contrast, genetic studies of non-model, natural populations are desirable as they provide a wider range of adaptive phenotypes throughout evolutionary timescales and allow a more realistic understanding of how natural selection drives adaptive evolution. This thesis represents an example of how modern genomic tools can be effectively used to study adaptation in natural populations. Atlantic herring is one of the world’s most numerous fish having multiple populations with phenotypic differences adapted to strikingly different environments. Our study demonstrated insignificant level of genetic drift in herring that resulted in minute genetic differences in the majority of the genome among these populations. In contrast, a small percentage of the loci showed striking genetic differentiation that were potentially under natural selection. We identified loci associated with adaptation to the Baltic Sea and with seasonal reproduction (spring- and autumn-spawning) and demonstrated that ecological adaptation in Atlantic herring is highly polygenic but controlled by a finite number of loci. The study of Darwin’s finches constitutes a breakthrough in characterizing their evolution. We identified two loci, ALX1 and HMGA2, which most likely are the two most prominent loci that contributed to beak diversification and thereby to expanded food utilization. These loci have played a key role in adaptive evolution of Darwin’s finches. Our study also demonstrated that interspecies gene flow played a significant role in the radiation of Darwin’s finches and some species have a mixed ancestry. This thesis also explored the genetic basis for the remarkable phenotypic differences between three male morphs in the ruff. Identification of two different versions of a 4.5 MB inversion in Satellites and Faeders that occurred about 4 million years ago revealed clues about the genetic foundation of male mating strategies in ruff. We highlighted two genes in the inverted region; HSD17B2 that affects metabolism of testosterone and MC1R that has a key role in regulating pigmentation, as the major loci associated with this adaptation.
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ROS, GLORIA. "ROLE OF HMGA1 IN BREAST CANCER AGGRESSIVENESS." Doctoral thesis, Università degli Studi di Trieste, 2016. http://hdl.handle.net/11368/2908068.
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Breast cancer is the most common cancer in women and a leading cause of cancer mortality worldwide, mainly due to metastatic progression. Although in the last years cancer has become more curable, the path to eradicate it, is still long and convolute. Understanding molecular mechanisms that induce and support cancer progression and aggressiveness is crucial to find new targets and drugs to treat it. High Mobility Group A1 (HMGA1) protein is an oncofetal architectural chromatin factor that promotes neoplastic transformation and progression but its role in breast cancer aggressiveness is still unclear. The aim of this thesis was to unravel the involvement of HMGA1 in this disease highlighting which pathways are intersected. Thus, working on basal-like breast cancer subtype, we demonstrated that HMGA1 plays a crucial role in conferring metastatic traits. Indeed, HMGA1 silencing reduces migration and invasion properties in vitro and metastasis formation in vivo with a concomitant mesenchymal to epithelial transition and decreases stem cell properties and self-renewal activity. We performed microarray analysis in cells expressing or depleted for HMGA1 and we identified a specific 130-HMGA1 gene signature associated with poor prognosis. This analysis allowed us to identify pathways, controlled by HMGA1 and known to be involved in aggressiveness traits, such as Wnt/beta-catenin and Notch. Moreover, among the genes present in the 130-HMGA1 gene signature we deepen the relationship between HMGA1 and CCNE2, one of the gene most correlated with clinical outcome. We showed that CCNE2 acts downstream HMGA1 to regulate the migration and invasion proprieties of basal-like breast cancer cells. Moreover, we demonstrated that CCNE2 action is mediated by the oncogene YAP, the downstream effector of the Hippo pathway. Indeed, knock down of both HMGA1 and CCNE2 impaired nuclear localization and activity of YAP, acting upstream of the Hippo pathway core kinases MST1/2 and LATS1/2. Moreover, in breast cancer patients, HMGA1 and CCNE2 expression was associated with YAP/TAZ signature further supporting this connection. Because CDKs are the main partners of CCNE2, we blocked their activity using CDK inhibitors in order to impair HMGA1-CCNE2-YAP axis and we demonstrated a decrease in cell migration and an induction of translocation of YAP from nucleus to cytoplasm. Therefore, this thesis highlights the involvement of HMGA1 in breast cancer metastasis through the interplay with different pathways. In particular, we identified for the first time a role of HMGA1 in regulating YAP through the modulation of the Hippo pathway.
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Beitzel, Brett F. "The role of HMGA proteins in retroviral integration /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3099924.
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Arnoldo, Laura. "HMGA1 proteins regulate gene expression by modulating histone H3 phosphorylation." Doctoral thesis, Università degli studi di Trieste, 2014. http://hdl.handle.net/10077/10112.
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2012/2013HMGA1 is an oncogene encoding for an architectural transcription factor that affects fundamental cell processes, leading to neoplastic transformation. The two main mechanisms by which HMGA1 protein is known to be involved in cancer concern the regulation of gene expression by altering DNA structure and interacting with a conspicuous number of transcription factors. Here we provide evidence of an additional level of gene expression regulation exploited by HMGA1 to exert its oncogenic activity. Starting from protein-protein interaction data showing that HMGA1 interacts with histones, we show that HMGA1 regulates gene expression by affecting the epigenetic status of cancer cells. In particular, it modulates the signalling cascade mediated by the RAS/RAF/MEKK/ERK/RSK2 pathway regulating the levels of histone H3 phosphorylation at Serine 10 and Serine 28. We demonstrate that the down-regulation of these two H3 post-translational modifications by HMGA1 silencing and by inhibitors of the RAS/RAF/MEKK/ERK pathway is linked to cell migration decrease and morphological changes resembling the mesenchymal to epithelial transition.
HMGA1 è un oncogene codificante per un fattore trascrizionale architetturale che influenza fondamentali processi cellulari, portando alla trasformazione neoplastica. I due principali meccanismi tramite cui la proteina HMGA1 è nota essere coinvolta nel cancro riguardano la regolazione dell’espressione genica tramite l’alterazione della struttura del DNA e l’interazione con un cospicuo numero di fattori di trascrizione. Qui forniamo la prova di un addizionale livello di regolazione dell’espressione genica sfruttato da HMGA1 per esercitare la sua attività oncogenica. Partendo da dati d’interazione proteina-proteina che mostrano che HMGA1 interagisce con gli istoni, mostriamo che HMGA1 regola l’espressione genica influenzando lo stato epigenetico delle cellule cancerose. In particolare, essa modula la cascata di segnalazione mediata dalla via di RAS/RAF/MEKK/ERK/RSK2 regolando i livelli di fosforilazione dell’istone H3 sulla Serina 10 e sulla Serina 28. Noi dimostriamo che la down-regolazione di queste due modificazioni post-traduzionali di H3 tramite il silenziamento di HMGA1 e l’utilizzo di inibitori della via di RAS/RAF/MEKK/ERK/RSK2 è correlata alla diminuzione della migrazione cellulare e a cambiamenti morfologici che ricordano la transizione mesenchimo-epiteliale.
XXV Ciclo
1983
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Eren, Elif. "HMA2. A Transmembrane Zn2+ Transporting ATPase from Arabidopsis thaliana." Worcester, Mass. : Worcester Polytechnic Institute, 2007. http://www.wpi.edu/Pubs/ETD/Available/etd-010507-150007/.
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Pellarin, Ilenia. "HMGA PROTEINS IN EPITHELIAL-MESENCHYMAL TRANSITION AND TUMOUR PROGRESSION." Doctoral thesis, Università degli studi di Trieste, 2014. http://hdl.handle.net/10077/10117.
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2012/2013High Mobility Group A (HMGA1a, HMGA1b and HMGA2) proteins are architectural nuclear factors, physiological expressed during embryonic development and re-expressed at high levels following neoplastic transformation, playing essential functions in both these processes thanks to their particular plasticity and consequently multifunctionality. HMGA are involved in a wide number of cellular processes, including Epithelial-Mesenchymal transition (EMT), a biologic developmental process characterized by the conversion of epithelial cells to motile mesenchymal ones, with increased capacity of migration and invasion. EMT plays a key role during the progression of different tumours, including breast cancer and also HMGA have been linked to these processes in the acquisition of tumourigenic features. Consequently taking advantage of different breast cancer cell lines to recreate an "EMT model" we have investigated the role of HMGA proteins in EMT and breast carcinoma. We have developed a cellular model, stable for the overexpression of HMGA1 using the human breast cancer cell line MCF7. We have explored different aspects of tumourigenesis, performing transwell migration and invasion assays, demonstrating that cells with high levels of HMGA1 migrate and invade at a higher and significant level in comparison to control cells. Moreover this data was also confirmed with the development of an inducible cell line for HMGA1 overexpression. Therefore we have examined the expression status of different genes, including several specific EMT markers at mRNA level with Real Time PCR, observing a pre-malignant change towards mesenchymal status. We have investigated the response after DNA damage induced by doxorubicin drug, by colony formation assay, demonstrating that HMGA1 overexpressing cells confer a survival advantage to the cells, being able to survive and form a significant higher number of colonies in respect to control cells. Therefore to study deeper the role of HMGA in EMT, we have developed other two cellular systems, a human cellular model of EMT in MDA-MB-468 human breast carcinoma cells treated with Epidermal Growth Factor (EGF) and the well known EMT model, elicited by Transforming Growth Factor-β (TGF-β) in murine mammary epithelial NMuMG cells, in which HMGA2 is functionally determinant. We have demonstrated by Real Time PCR of EMT markers, Western Blot analyses and immunofluorescence the effective reliability of these cellular models, confirmed also by a dramatic change in morphology of treated cells, towards a mesenchymal phenotype. Concluding we have interestingly observed that overexpression of HMGA1 could confer some tumourigenic features (i.e. migration, invasion) and survival advantage to the cells in the MCF7 model after a cellular DNA damage induction; therefore we have different suggestions that HMGA are involved in EMT in other different cellular models.
Le proteine HMGA (HMGA1a, HMGA1b e HMGA2), definite come fattori architetturali della cromatina, sono fisiologicamente espresse ad alti livelli nel corso dello sviluppo embrionale diminuendo gradualmente la loro espressione nel corso del differenziamento. Sono coinvolte, oltre all'aspetto fisiologico, anche in diverse condizioni patologiche, essendo ad esempio ri-espresse ad alti livelli nel corso della trasformazione neoplastica, esercitando funzioni essenziali grazie alla loro alta plasticità, alle peculiari caratteristiche biochimiche e conseguente multifunzionalità. Le proteine HMGA utilizzano diversi meccanismi per esercitare la loro funzione nell'acquisire capacità trasformanti, inclusa la transizione epitelio-mesenchimale. Questo processo biologico, primariamente identificato come fattore chiave dello sviluppo embrionale, è risultato di essere di fondamentale importanza anche nella trasformazione tumorale. Mediante questo meccanismo una cellula epiteliale, mediante molteplici cambiamenti genetici e biochimici acquisisce caratteristiche tipiche di uno "stato mesenchimale", caratterizzato ad esempio da un'aumentata capacità invasiva e migratoria. La transizione epitelio-mesenchimale esercita un ruolo chiave nel corso della progressione di diverse tipologie tumorali, incluso il cancro al seno, a cui in particolare anche le proteine HMGA sono state associate. L'obiettivo della Tesi è quindi quello di studiare il ruolo delle proteine HMGA nella transizione epitelio-mesenchimale e in particolare nel cancro al seno. A questo scopo abbiamo sviluppato diversi modelli cellulari di transizione epitelio-mesenchimale. Il primo modello ha previsto la creazione di un sistema stabile di over-espressione della proteina HMGA1 nella linea epiteliale di tumore al seno MCF7. Abbiamo analizzato diversi aspetti della tumorigenesi mediante saggi di migrazione ed invasione in transwell, dimostrando come alti livelli della proteina HMGA1 inducano un aumento di entrambi i processi rispetto ad una condizione di controllo. Inoltre i dati di migrazione sono stati confermati in un sistema inducibile per la over-espressione di HMGA1 nella stessa linea cellulare MCF7 e da saggi condotti in condizione di deplezione di HMGA1 attraverso strategie di silenziamento, dimostrando ulteriormente come la migrazione sia un fenomeno HMGA1 dipendente. Abbiamo inoltre esaminato lo stato di espressione di diversi geni, inclusi specifici marker di transizione epitelio-mesenchimale, mediante analisi di Real Time PCR, osservando un cambiamento verso una condizione di tipo pre-maligno e di parziale transizione ad uno stato mesenchimale. Inoltre è stata verificata la risposta al danno indotto da doxorubicina mediante saggio di colony formation, dimostrando come cellule over-esprimenti HMGA1 possiedano un vantaggio in termini di sopravvivenza e di numero di colonie formate, rispetto alle cellule di controllo. Per approfondire ulteriormente il ruolo esercitato dalle HMGA nella transizione epitelio-mesenchimale, sono stati sviluppati altri due modelli cellulari, uno nella linea epiteliale umana di cancro al seno MDA-MB-468 trattata con EGF (Epidermal Growth Factor), l'altro nella linea cellulare murina mammaria di tipo epiteliale NMuMG, trattata con TGF-β (Transforming Growth Factor-β), in cui l'azione di HMGA2 è stato dimostrato avere un ruolo determinante. Mediante analisi di Real Time PCR di marker di transizione epitelio-mesenchimale, di Western Blot e di immunofluorescenza abbiamo dimostrato l'effettiva solidità di questi modelli cellulari, confermato anche dal fatto che è possibile apprezzare un consistente cambio morfologico verso un fenotipo mesenchimale e una concomitante over-espressione delle proteine HMGA. Da questi modelli è stato quindi possibile evincere come le HMGA siano coinvolte nell'acquisizione di caratteristiche di tipo tumorale anche mediante processi di transizione epitelio-mesenchimale e come questi modelli siano utili al fine di semplificare network molecolari.
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ALTAMURA, SANDRO. "IDENTIFICAZIONE E CARATTERIZZAZIONE DI PARTNERS MOLECOLARI DELLE PROTEINE HMGA." Doctoral thesis, Università degli studi di Trieste, 2007. http://thesis2.sba.units.it/store/handle/item/12290.
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Adair, Jennifer Eileen. "Molecular and genetic influence of HMGA1 proteins on nucleotide excision repair." Online access for everyone, 2005. http://www.dissertations.wsu.edu/Dissertations/Fall2005/j%5Fadair%5F120605.pdf.
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Vogel, Benjamin [Verfasser], and Robert [Akademischer Betreuer] Hock. "Organisation von Chromatin durch HMGA1 Proteine / Benjamin Vogel. Betreuer: Robert Hock." Würzburg : Universitätsbibliothek der Universität Würzburg, 2012. http://d-nb.info/1025223853/34.
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SGUBIN, MICHELA. "HMGA1-p27-stathmin axis promotes migration in triple-negative breast cancer cells." Doctoral thesis, Università degli Studi di Trieste, 2020. http://hdl.handle.net/11368/2961109.
Full textAbstract:
My research project focused on Triple Negative Breast Cancer (TNBC), which is the most aggressive breast cancer subtype, characterized by the absence of ER, PR and HER2 receptors. Up to now, no targeted therapeutic opportunities for patients are available. One of the key players in the promotion of TNBC aggressiveness is the oncofetal protein HMGA1, an architectural chromatin factor involved in the regulation of gene transcription. In this work we aimed to identify the molecular pathways through which HMGA1 could promote invasiveness in TNBC. By bioinformatic analysis in a cohort of TCGA breast cancer samples, we found an inverse correlation between HMGA1 expression and p27 protein, a well-known CDK inhibitor that has CDK-independent cytoplasmic functions such as the modulation of cell migration. Moreover, in patients with high levels of HMGA1, we observed an enrichment in the expression of a molecular partner of p27, the microtubule-destabilizing protein stathmin. Then, we confirmed the functional relationship observed by TCGA analysis demonstrating that p27 was upregulated at the protein level following the silencing of HMGA1 in two TNBC cell lines (MDA-MB-231 and MDA-MB-157), while stathmin was down-modulated. Moreover, via qRT-PCR, we observed that p27 mRNA level was not modulated by HMGA1, implying a post-translational level of regulation. In fact, by cycloheximide assay, we showed that p27 protein was stabilized after HMGA1 silencing. Moreover, we found that p27 localized in the cytoplasm and, after HMGA1 depletion, was phosphorylated in the cytoplasmic-retaining sites S10 and T198. Looking at stathmin involvement in TNBC, we determined that it is implicated in the promotion of MDA-MB-231 microtubule dynamicity and migration. By silencing the expression of HMGA1 in the same cell line, we demonstrated that stathmin diminishes its interaction with tubulin and it is responsible of motility promotion downstream HMGA1. Thus, we co-silenced HMGA1, p27 and stathmin in MDA-MB-231 cells and we analysed the trans-well migratory abilities of cells showing that HMGA1 promotes the migration through the regulation of p27 and stathmin. One of the chemotherapeutic drugs in the first line treatment for TNBC is paclitaxel, an antineoplastic drug that acts interfering with microtubule function. In literature, both HMGA1 and stathmin have been shown to be involved in paclitaxel chemoresistance. Therefore, we tried to sensitize TNBC cells by targeting the HMGA1-p27-stathmin axis. Upon HMGA1-silencing of MDA-MB-231 cells, we were able to reduce the motility of cells treated with paclitaxel, sensitizing them to the treatment. Finally, we determined that the HMGA1 depletion in MDA-MB-231 cells injected in the mammary fat pad of nude mice, was able to sensitize the primary tumor volume to paclitaxel treatments.
Overall, we identify an HMGA1/p27/stathmin axis involved in the promotion of migration that could be considered as a possible target in combination with standard paclitaxel chemotherapy in TNBC patients.
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Eren, Elif. "HMA2. A Transmembrane Zn2+ Transporting ATPase from Arabidopsis thaliana." Digital WPI, 2007. https://digitalcommons.wpi.edu/etd-dissertations/6.
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P1B-type ATPases transport a number of monovalent and divalent heavy metals (Cu+, Cu2+, Ag+, Zn2+, Cd2+, Pb2+ and Co+2) across biological membranes. These ATPases are found in archea, bacteria and eukaryotes and are one of the key elements required for maintaining metal homeostasis. Plants have an unusually high number of P1B-type ATPases with distinct metal selectivity compared to other eukaryotes that usually have one or two Cu+-ATPases. Higher plants are the only eukaryotes where Zn2+-ATPases have been identified. Towards understanding the physiological roles of plant Zn2+-ATPases, we characterized Arabidopsis thaliana HMA2. We expressed HMA2 in yeast and measured the metal dependent ATPase activity in membranes. We showed that HMA2 is a Zn2+-ATPase that is also activated by Cd2+. Zn2+ transport determinations showed that this enzyme drives the efflux of metal from the cytoplasm. Analysis of HMA2 mRNA levels showed that the enzyme is present in all plant organs. We analyzed the effect of removal of HMA2 full-length transcript in whole plants by gene knock out. Although hma2 mutants did not show a different visible phenotype from the wild type plants, we observed increased levels of Zn2+ or Cd2+. The observed phenotype of hma2 mutants and plasma membrane location of HMA2, mainly in vasculature (Hussain et al., 2004), indicates that this ATPase might have a central role in Zn2+ uploading into the phloem. P1B-type ATPases have cytoplasmic regulatory metal binding domains (MBDs) in addition to transmembrane metal binding sites (TMBDs). Plant Zn2+-ATPases have distinct sequences in both their N- and C-termini that might contribute to novel metal binding sites. These ATPases contain long C-terminal sequences rich in CC dipeptides and His repeats. Removal of the C-terminus (C-MBD) of HMA2 leads to a 50% reduction in the enzyme turnover suggesting a regulatory role for this domain. Atomic Absorption Spectroscopy (AAS) analysis showed that Zn2+ binds to C-MBD with a stoichiometry of three (3 Zn/C-MBD). Chemical modification studies and Zn K-edge X-ray Absorption Spectroscopy (XAS) of Zn-C-MBD showed that Zn2+ is likely coordinated by His in two sites and the third site slightly differs from the others involving a Cys together with three His. All plant Zn2+-ATPases lack the typical CXXC signature sequences observed in Cu+-ATPases and some bacterial Zn2+-ATPases N-terminus metal binding domains (N-MBDs). Instead, these have conserved CCXXE sequences. Truncation of HMA2 N-MBD results in a 50% decrease in enzyme Vmax suggesting that N-MBD is also a regulatory domain. The results indicate that the N-MBD binds Zn2+ with a stoichiometry of one (1 Zn/N-MBD). Metal binding analysis of individual N-MBD mutants Cys17Ala, Cys18Ala and Glu21Ala/Cys prevented Zn+2 binding to HMA2 N-MBD suggesting the involvement of all these residues in metal coordination. ATPase activity measurements with HMA2 carrying the mutations Cys17Ala, Cys18Ala and Glu21Ala/Cys showed a reduction in the enzyme activity similar to that observed the truncated protein indicating that the enzyme activity reduction observed in the N-terminus truncated forms of the enzyme is related to the removal of the metal binding capability. Summaryzing, these studies show the central role of HMA2 in plant Zn2+ homeostasis. They also describe the mechanism and direction of Zn2+ transport. Finally, they establish the presence of novel metal binding domains in the cytoplasmic portion of the enzyme. Metal binding to these domains is required for full enzymatic activity.
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Beuing, Claudia [Verfasser]. "Charakterisierung des Caninen High – Mobility – Group A1 (HMGA1) Gens und Detektion von Punktmutationen / Claudia Beuing." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2010. http://d-nb.info/1009589687/34.
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Liau, Siong Seng. "High mobility group A1 (HMGA1) : a novel prognostic indicator and therapeutic target in pancreatic adenocarcinoma." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/24834.
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We hypothesised that HMGA1 is overexpressed in pancreatic cancers and plays a role in the malignant phenotype of pancreatic cancer cells. There are two broad components to this work: to examine the expression of HMGA1 in pancreatic cancer tissues from patients who underwent reaction and to assess if HMGA1 expression could be used as a prognostic biomarker; and to address the roles of HMGA1 in the pancreatic cancer progression, and assess the effects of therapeutic targeting of HMGA1 in experimental pancreatic cancer models. We showed that HMGA1 is overexpressed in more than 90% of pancreatic cancers and is associated with poorer postoperative survival. Tumoural HMGA1 expression was found to be an independent prognostic indicator in patients who underwent resection. Our in vitro studies suggest that HMGA1 promotes cellular invasiveness in pancreatic cancer cells through PI3-K/Akt-dependent MMP9 expression. Post-transcriptional silencing of HMGA1 suppressed metastasis in vivo. Overexpression of HMGA1 promotes PI3-K/Akt-dependent anoikis resistance and anchorage independent proliferation. The regulatory role of HMGA1 on the PI3-K/Akt pathway is novel and previously undescribed. Although HMGA1 also regulates ERK activity, the contribution of this pathway is less important in the HMGA1-induced anchorage-independent growth. In vivo silencing of HMGA1 resulted in attenuation of tumour growth in xenograft mouse model. HMGA1 represents a novel molecular determinant of chemoresistance to gemcitabine in pancreatic cancer cells. Targeted silencing of HMGA1 chemosensitised pancreatic cancer cells to gemcitabine both in vitro and in vivo. Targeting of HMGA1 may be a novel therapeutic (anti-metastatic, anti-proliferative and chemosensitising) strategy to ameliorate the aggressive phenotype of pancreatic cancer cells.
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ZANIN, ROSSELLA. "HMGA1 AND FOXM1 SYNERGISTICALLY REGULATE A COMMON GENE NETWORK MODULATING THE ANGIOGENESIS IN BREAST CANCER." Doctoral thesis, Università degli Studi di Trieste, 2018. http://hdl.handle.net/11368/2924772.
Full textAbstract:
My research project was focused on the study of triple negative breast cancer (TNBC), which is highly aggressive and unresponsive to common treatments. One of the factors responsible for the aggressive features of TNBC is the High mobility group A1 (HMGA1) protein, a master regulator of the gene transcription, whose high expression level has been correlated with a higher grade in breast cancer. To deepen the knowledge about HMGA1 in breast cancer, we sequenced the RNA collected from a model of TNBC, the MDA-MB-231 cell line, upon HMGA1 silencing; thanks to a bioinformatic analysis, we unraveled molecular partners HMGA1 could cooperate with in regulating common downstream gene networks in breast cancer and among them we selected Forkhead box M1 (FOXM1) transcription factor, chosen for its role in breast carcinogenesis. Firstly, we validated several HMGA1/FOXM1 targets by qRT-PCR after HMGA1 and FOXM1 silencing in TNBC cell lines. Moreover, the depletion of FOXM1 in TNBC cells leads to the acquisition of a more epithelial-like phenotype, with a disruption of the vimentin network, a typical marker of mesenchymal phenotype, results similar to those we obtained upon HMGA1 silencing, and further accentuated by the co-silencing of the two factors. In addition, upon HMGA1 depletion in TNBC cell lines and HEK-293T, FOXM1 translocates from the nucleus to the cytoplasm, suggesting that HMGA1 could modulate FOXM1 subcellular localization and activity. To validate this hypothesis, we performed a luciferase reporter assay, by transfecting the HEK293T cells with a construct containing a portion of the promoter of a known HMGA1/FOXM1 target, the Vascular Endothelial growth factor A (VEGFA). By co-transfecting the two factors, we found that HMGA1 increases the transcriptional activity of FOXM1 on VEGFA promoter and with several deletion constructs we restricted the region responsible for this activity. Considering that the VEGFA is one of the main inducer of angiogenesis, a hallmark in breast cancer, we investigated how HMGA1 and FOXM1 are involved. Firstly, we demonstrated that the amount of VEGFA secreted by MDA-MB-231 cells after HMGA1 silencing is decreased. Afterwards, we treated the HUVEC endothelial cells with supernatants of MDA-MB-231 depleted of HMGA1 and/or FOXM1 and we observed that the proliferation, the migration, and the ability to form a vessel-like network of HUVEC cells were affected. We finally validated in vivo that HMGA1 and FOXM1 synergistically regulate the neo-angiogenesis in Zebrafish larvae. Hence, we demonstrated that HMGA1 and FOXM1 are involved in the regulation of the same gene network in TNBC and that HMGA1 influences the FOXM1 cellular localization and transcriptional activity. We showed also that the tumor cells, on the driving force of HMGA1 and FOXM1, modulate the angiogenic process carried out by endothelial cells, both in vitro and in vivo.
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Jakimovska, Frosina. "Characterization of the interaction between nucleophosmin (NPM) and highmobility group a (HMGA) proteins." Doctoral thesis, Università degli studi di Trieste, 2008. http://hdl.handle.net/10077/2760.
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2006/2007ABSTRACT HMGA proteins are members of the high mobility group (HMG) non-histone, architectural chromosomal proteins. The HMGA family consists of: A1a, A1b and A2, the first two being isoforms produced by alternative splicing. These are small proteins, about 100aa residues long, characterized by three basic stretches of AT-hooks which bind to the AT-rich sequences on the DNA minor groove. They are normally present in rapidly proliferating cells (embryo) whereas upon differentiation the levels of these proteins decrease until they are nearly absent from adult cells. Overexpression of these proteins has been correlated with various types of neoplastic transformations. The interaction network of HMGA has been an object of study for years in our laboratory and one of the most intriguing protein-protein interactions studied is the one between HMGA and nucleophosmin. Nucleophosmin (NPM, B23, numatrin or NO38) is one of the most abundant phosphoproteins, mainly localized in the nucleoli but it also shuttles between the nucleus and the cytoplasm. This versatile protein has been proven to be involved in various cellular functions and related to both proliferative and growth-suppressive roles in the cell. The first evidence of the interaction HMGA2-NPM in our lab has been obtained by in vitro assays (affinity chromatography). The step ahead was to see if this interaction occurs in vivo and if it does, to try to find ts functional significance. Thus,immunoprecipitation (IP) experiments were performed.The first one gave the proof thet interaction between HMGA2 protein and NPM (transfected and endogenous) occurs. The second IP gave the evidence that interaction occurs between HMGA1a and NPM too. This in vivo protein-protein interaction was to be given a functional significance. We tested by siRNA HMGA1a treatment if downregulation of HMGA1a expression influences the expression of the SOD2 gene (regulated by NPM). The effect of the HMGA1a silencing has proven to be very slight on the SOD2 gene (a 14% of expression reduction). EMSA experiments have been performed in order to test the effect of NPM on the DNA binding properties of the HMGA2 protein with the DNA probes E3 and HCRII. In both cases it has been observed that NPM increases the DNA binding affinity of the HMGA2 protein.
1979
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Zammitti, Salvina. "Post-translational modifications of high mobility group a (HMGA) proteins in neoplastic transformation." Doctoral thesis, Università degli studi di Trieste, 2010. http://hdl.handle.net/10077/3614.
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2008/2009Le proteine HMG (High Mobility Group) sono la famiglia più ampiamente e meglio caratterizata fra le proteine cromosomiche non istoniche. Esse sono raggruppate in tre sottofamiglie: HMGA, HMGB ed HMGN. Ciascuna sottofamiglia è caraterizzata da una sequenza o motivo funzionale attraverso il quale sono capaci di legarsi a specifiche strutture sul DNA o sulla cromatina. La famiglia HMGA di mammifero consiste di due geni funzionali: HMGA1 and HMGA2. Lo splicing alternativo del trascritto del gene HMGA1 dà origine alle proteine HMGA1a ed HMGA1b. La proteina HMGA2 è codificata dall’altro gene. Le proteine HMGA partecipano a specifiche interazioni proteina-DNA e proteina-proteina inducendo sia cambiamenti strutturali della cromatina che la formazione di complessi macromolecolari su regioni promotrici//enhancer di diversi geni. Pertanto esse sono descritte come fattori archietturali della trascrizione. Grazie alla loro multifunzionalità, ese partecipano a diversi processi biologici quali l’integrazione virale, l’embriogenesi e la differenziazione, l’apoptosi, la senescenza, la trasformazione neoplastica ed il riparo del DNA. La caratteristica di proteine oncofetali attribuita alle HMGA prende origine dal fatto che esse sono (i) altamente espresse durante l’embriogenesi, (ii) assenti o espresse a bassi livelli nei tessuti adulti e (iii) altamente riespresse nelle cellule trasformate. Queste proteine sono, tra le proteine nucleari, quelle più soggette a modificazioni post-traduzionali e le loro attività sono modulate da una ampia varietà di modificazioni post-traduzionali. In questo lavoro di tesi, grazie all’uso di linee cellulari di cancro mammario in cui è stata indotta la reversione del fenotipo neoplastico tramite trattamento farmacologico e successive analisi di spettrometria di massa, si è ricercata una connessione tra le modificazioni post-traduzionali delle HMGA ed il processo di trasformazione neoplastica. Inoltre, grazie ad una nuova strategia in vitro sviluppata nel nostro laboratorio per l’identificazione di partner molecolari delle proteine HMGA, si è dimostrato che la proteina HMGA1a si associa con la proteina Ku70, che è un fattore chiave coinvolto nel riparo delle rotture al doppio filamento di DNA attraverso il “non-homologous end joining”. Numerose evidenze sperimentali suggeriscono che l’inibizione del riparo del DNA da parte delle HMGA posa contribuire alle instabilità genetiche e cromosomiche comunemente ritrovate nelle celle cancerose. Perciò, si è ricercata una relazione funzionale tra le proteine HMGA e le proteine chiave nel meccanismo di riparo del DNA attraverso “non-homologous end joining”, focalizzando l’attenzione in particolare sulla proteina DNA-PK (DNA-dependent protein kinase), che ha una funzione regolatrice chiave in questo processo.
XXII Ciclo
1973
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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.
Full textAbstract:
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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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/.
Full textAbstract:
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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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.
Full textAbstract:
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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Shama, Bansod. "Hes5 regulates the transition timing of neurogenesis and gliogenesis in mammalian neocortical development." Kyoto University, 2017. http://hdl.handle.net/2433/228230.
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Bloch, Mandy [Verfasser]. "HMGA1- als neuer Koregulator der Peroxisomen Proliferator aktivierten Rezeptor gamma- vermittelten Transrepression in humanen Gefäßmuskelzellen / Mandy Bloch." Berlin : Freie Universität Berlin, 2013. http://d-nb.info/1037343069/34.
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PETROSINO, SARA. "HMGA1 MODULA L'ESPRESSIONE DEGLI ISTONI CICLO CELLULARE-DIPENDENTE, RENDENDO CELLULE RESISTENTI ALL'EPIRUBICINA PIU' SENSIBILI ALLA SUA AZIONE." Doctoral thesis, Università degli Studi di Trieste, 2021. http://hdl.handle.net/11368/2988916.
Full textAbstract:
Il mio progetto si è focalizzato sullo studio di un sottotipo di cancro al seno, il triplo negativo (TN), il più aggressivo e difficile da trattare per l'assenza di opzioni terapeutiche specifiche diverse dalla chemioterapia. Di solito, la terapia adiuvante (cioè regimi a base di antracicline) è raccomandata dopo l'intervento chirurgico di pazienti affetti da TN. HMGA1 è una proteina oncofetale coinvolta nell'insorgenza e nella progressione della trasformazione neoplastica e nella chemioresistenza. HMGA1 è un fattore oncogenico chiave nel TN coinvolto nei meccanismi di regolazione trascrizionale ed epigenetica. Il nostro gruppo di ricerca ha dimostrato che HMGA1 può influenzare lo stato di fosforilazione dell'istone H1 nelle cellule TNBC poiché il silenziamento di HMGA1 porta alla defosforilazione dell'istone H1.In questa tesi abbiamo indagato questa regolazione. Infatti, abbiamo eseguito analisi LC / MS dell'istone H1 dopo il silenziamento di CCNE2 e CDK2, i principali fattori responsabili della sua fosforilazione.Abbiamo dimostrato che la modulazione HMGA1 della fosforilazione dell'istone H1 passa attraverso un meccanismo dipendente da cyclinE2-Cdk2. Poiché la fosforilazione dell'istone H1 è dipendente dal ciclo cellulare abbiamo ipotizzato che HMGA1 potesse avere un ruolo nella modulazione del ciclo cellulare degli istoni. Abbiamo proceduto con l'analisi dell'espressione genica e proteica in cellule TN, silenziate per l'espressione di HMGA1. Di conseguenza, abbiamo valutato una diminuzione dell'espressione degli istoni a livelli trascrizionali e post-trascrizionali in queste condizioni. Quindi, abbiamo approfondito l'ipotesi di una via dipendente da HMGA1 per l'espressione genica degli istoni. Abbiamo dimostrato che HMGA1 regola direttamente l'espressione dell’ istone HIST1H4H attivando il suo promotore. Inoltre, abbiamo constatato un'interazione proteina / proteina tra HMGA1 e NPAT, un regolatore principale dell'espressione trascrizionale dell'istone. Successivamente, abbiamo analizzato la distribuzione del ciclo cellulare delle cellule MDA-MB-231 dopo il silenziamento di HMGA1 mediante citometria a flusso. Pertanto, abbiamo dimostrato che HMGA1 promuove la progressione del ciclo cellulare nelle cellule MDA-MB-231 e il suo silenziamento riduce l'espressione proteica di SLBP, un sensore della progressione del ciclo cellulare. Quindi, abbiamo sfruttato analisi bioinformatiche per ottenere il valore prognostico e predittivo degli istoni regolati da HMGA1 in BC. Abbiamo verificato che specifiche varianti istoniche sono arricchite significativamente (HIST1H1C / H1.2, HIST1H2AC / H2A1c, HIST1H2BD / H2B1d e HIST1H4H / H4) in tessutu tumorali di cancro al seno e TN. Abbiamo osservato che HIST1H1C / H1.2 e HIST1H4H / H1.4 hanno anche un valore prognostico . Sulla base delle attuali terapie e della nostra evidenza sperimentale con cui dimostriamo che l'espressione di HMGA1 influenza la distribuzione del ciclo cellulare in MDA-MB-231, ci siamo chiesti se HMGA1 potesse essere un fattore chemiosensibilizzante per un farmaco contro cellule attivamente proliferanti come l'epirubicina. A tal fine, abbiamo generato una linea cellulare TNBC resistente all'epirubicina (ER-TNBC) utilizzando cellule MDA-MB-231 (ER-MDA-MB-231). Con il saggio MTS abbiamo dimostrato che HMGA1 è un fattore chemiosensibilizzante per l'azione citotossica dell'epirubicina. Dopo abbiamo eseguito l'analisi della distribuzione del ciclo cellulare delle cellule ER-MDA-MB-231 mediante citometria a flusso dopo silenziamento di HMGA1 rispetto al controllo. Abbiamo concluso che HMGA1 favorisce l'effetto citotossico dell'epirubicina attraverso il coordinamento della proliferazione cellulare. Infatti, abbiamo dimostrato che HMGA1 promuove la progressione del ciclo cellulare nelle cellule ER-MDA-MB-231. Pertanto, concludiamo che l'espressione di HMGA1 non può essere trascurata nei regimi di trattamento con epirubicina per cellule tumorali esprimenti HMGA1.My research project is focused on the study of a specific subtype of breast cancer (BC), the triple-negative (TNBC), the most aggressive and difficult to treat because of the absence of specific therapeutic options other than chemotherapy. Usually, adjuvant therapy (i.e anthracycline-based regimens) is recommended after surgical intervention of patients affected by TNBC. HMGA1 is involved in the onset and progression of neoplastic transformation, and in chemoresistance. HMGA1 is a key oncogenic factor in TNBC involved in transcriptional and epigenetic regulatory mechanisms. We already demonstrated that HMGA1 can affect histone H1 phosphorylation status in TNBC cells, since HMGA1 depletion leads to dephosphorylation of histone H1. In this thesis, we decided to elucidate the pathway leading to this regulation. Indeed, we performed LC/MS analyses of histone H1 extracted after CCNE2 and CDK2 silencing, the major factors responsible for histone H1 phosphorylation. We demonstrate that HMGA1 modulation of histone H1 phosphorylation goes through a cyclinE2-Cdk2 dependent mechanism. Since histone H1 phosphorylation is cell cycle-dependent and has low phosphorylation in G1-phase and an increased rate in S- and G2-phase with a maximum during mitosis, we hypothesized that HMGA1 could have a role in cell-cycle modulation of histones. We proceeded with histone gene and protein expression analyses in TNBC cells, silenced for HMGA1 expression. Accordingly, we evaluated a decrease in expression of histones at transcriptional and post-transcriptional levels after HMGA1 depletion in TNBC cells. Then, we deeper investigated the hypothesis of a HMGA1 dependent pathway for histone gene expression. We started focusing on specific histone variant (HIST1H4H/H4) modulated after HMGA1 silencing. We demonstrate that HMGA1 directly regulates HIST1H4H histones expression by activating its promoter. Moreover, we disclosed a protein/protein interaction between HMGA1 and NPAT, a master regulator of histone transcriptional expression. After, we analyzed the cell cycle distribution of MDA-MB-231 cells after HMGA1 silencing by flow cytometry. Therefore, we demonstrated that HMGA1 promotes cell-cycle progression in MDA-MB-231 cells and its depletion reduces protein expression of SLBP, a sensor of cell cycle progression. Then, we exploited bioinformatic analyses to search for prognostic and predictive value of HMGA1-regulated histones in BC. Interestingly, we disclosed significantly high expressed histone variants (HIST1H1C/H1.2, HIST1H2AC/H2A1c, HIST1H2BD/H2B1d and HIST1H4H/H4) in BC also enriched in TNBC. Moreover, we observed that HIST1H1C/H1.2 and HIST1H4H/H1.4 had a prognostic value in BC. On the current therapeutic trend and our experimental evidence by which we demonstrate that HMGA1 expression influence cell cycle distribution in MDA-MB-231, we asked whether HMGA1 could be a chemosensitizer factor for a cell-proliferating active drug such as epirubicin. To this end, we generated a TNBC cell line resistant to epirubicin (ER-TNBC) using MDA-MB-231 cells (ER-MDA-MB-231). By the MTS-assay we demonstrated that HMGA1 is a chemosensitizer factor for epirubicin cytotoxic action. After we performed the analysis of the cell cycle distribution of ER-MDA-MB-231 cells by flow cytometry after HMGA1 silencing with respect to control condition. We concluded that HMGA1 favours epirubicin cytotoxic effect through the coordination of the active proliferation. Indeed, we demonstrated that HMGA1 promotes cell-cycle progression in ER-MDA-MB-231 cells. Finally, HMGA1 is involved in epirubicin chemoresistance, at least partially, by affecting the expression of HIST1H4H/H1.4 histone (probably of other as well) and in this way of cell cycle progression. Therefore, we conclude that HMGA1 expression could not be neglected in epirubicin treatment regimens for TNBC-HMGA1 expressing cancer and that could be a valuable mean to predict epirubicin responsiveness in resistance BC cells.
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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.
Find full textAbstract:
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;