Dissertations / Theses: 'HMGA proteins'

1

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.

Full text

APA, Harvard, Vancouver, ISO, and other styles

2

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.

Full text

Abstract:

2012/2013
High 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.
XXV Ciclo
1984

APA, Harvard, Vancouver, ISO, and other styles

3

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.

Full text

Abstract:

2006/2007
ABSTRACT 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

APA, Harvard, Vancouver, ISO, and other styles

4

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.

Full text

Abstract:

2008/2009
Le 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

APA, Harvard, Vancouver, ISO, and other styles

5

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.

Full text

APA, Harvard, Vancouver, ISO, and other styles

6

Uesugi, Hiroko. "Prevalence and characterization of novel P-ANCA, antibodies to the high mobility group non-histone chromosomal proteins HMG1 and HMG2, in systemic rheumatic diseases." Kyoto University, 2000. http://hdl.handle.net/2433/151400.

Full text

APA, Harvard, Vancouver, ISO, and other styles

7

Ragab, Anan. "Genetic and functional studies on abundant Drosophila HMGB proteins." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615068.

Full text

APA, Harvard, Vancouver, ISO, and other styles

8

Zayed, Hatem. "Improvement of the sleeping beauty transposon system." [S.l. : s.n.], 2003. http://www.diss.fu-berlin.de/2003/243/index.html.

Full text

APA, Harvard, Vancouver, ISO, and other styles

9

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.

Full text

APA, Harvard, Vancouver, ISO, and other styles

10

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.

Full text

Abstract:

2012/2013
HMGA1 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

APA, Harvard, Vancouver, ISO, and other styles

11

Feng, Sandy. "The high mobility group proteins 14 and 17 and their interaction with nucleosomes." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.253971.

Full text

APA, Harvard, Vancouver, ISO, and other styles

12

Preston, Nicola Susan. "Structure and DNA binding of HMG boxes." Thesis, University of Portsmouth, 1996. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310386.

Full text

APA, Harvard, Vancouver, ISO, and other styles

13

Simpson, Andrew. "Non-histone protein HMG-2A and chromatin structure." Thesis, University of Cambridge, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359813.

Full text

APA, Harvard, Vancouver, ISO, and other styles

14

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.

Full text

APA, Harvard, Vancouver, ISO, and other styles

15

Park, Semi Ph D. Massachusetts Institute of Technology. "Understanding the functions of HMGB proteins in the mechanism of action of cisplatin." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/78437.

Full text

Abstract:

Thesis (Ph. D. in Inorganic chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2012.
Cataloged from PDF version of thesis. Vita.
Includes bibliographical references.
High mobility group box (HMGB) proteins are DNA-binding proteins that regulate many important DNA-related processes. They are known to recognize the major lesion present in cisplatin-modified DNA, and have been assumed to increase cisplatin cytotoxicity by "shielding" the damaged site from the cellular repair apparatus. This thesis will describe the work in the area of molecular biology and biochemistry to improve our understanding of the functions of HMGB proteins in the mechanism of action of cisplatin. In Chapter 1, the molecular biology of cisplatin and HMGB proteins is described based on previously reported in vivo and in vitro experiments. The interaction of HMGB proteins and platinated DNA is reviewed based on several structural studies of platinum-DNA adducts of cisplatin, HMG box motif, and the binding complex of the two. Several cell-based studies supporting a repair-shielding hypothesis, suggesting an inhibitory function of HMGB proteins in the repair of cisplatin damage will be introduced with a focus on HMGB1, the most vigorously investigated HMGB protein. Additionally, other HMGB 1-mediated processes that may be related to cisplatin-triggered cell death will be discussed. Lastly, the correlation between testis-specific HMGB proteins and the cisplatin hypersensitivity of testicular germ cell tumors will be discussed. Although some HMGB proteins including HMGB 1 inhibit the repair of platinated damage on DNA in vitro, experiments conducted in live cells reveal conflicting correlation between the expression level of HMGB1 and cisplatin cytotoxicity. Chapter 2 describes studies in cultured human cancer cells aimed at examining the intracellular repair of platinum-modified DNA and the influence of HMGB1 on the repair processes. The expression of HMGB1 is artificially down-regulated by RNAi. HeLa and A549 cell lines present different trends in cisplatin cytotoxicity upon HMGB1 knockdown. Intracellular repair of cisplatin is lower in knockdown cells regardless of the parental cell line. This result stands in opposition to what is expected from the repair-shielding hypothesis. In addition, the repair of different cisplatin adducts was investigated in fibroblast cells deficient in one of the nucleotide excision repair proteins in order to understand the repair mechanisms of each adduct. Chapter 3 presents an in vitro study investigating the redox-dependence of the binding interaction of HMGB1 to the cisplatin-1,2-d(GpG) intrastrand cross-link. Two cysteine residues in HMGB1 domain A form a reversible disulfide bond under mildly oxidizing conditions. Both HMGB 1 domain A and full-length HMGB 1 presented significantly weaker binding to a DNA probe containing a 1,2-d(GpG) intrastrand cross-link when in their oxidized state compared to their fully-reduced form. Mutagenesis studies on the cysteine residues revealed that this redoxdependence originates from disulfide bond formation. Footprinting analysis of a platinated DNA probe bound to oxidized or reduced domain A showed that the asymmetric binding mode of domain A to platinated DNA is not significantly altered by oxidation. These results suggest that the cellular redox environment can influence the interaction of HMGB 1 with the platinated DNA. In Chapter 4, the binding properties and repair inhibitory function of HMGB4 to cisplatin-modified DNA are described. Based on its testis-restricted expression profile and sequence similarity with HMGB 1, we propose that HMGB4 functions as a cisplatin cytotoxicity enhancer in TGCT. To verify this hypothesis, HMGB4 and its binding domains were generated recombinantly and interactions with cisplatin-modified DNA were investigated in vitro. The binding properties of HMGB4 are quite similar to those of HMGB 1 except for a few differences: i) full-length HMGB4 has stronger binding affinity than full-length HMGB1, because of a lack of a C-terminal acidic tail. ii) binding of HMGB4 domain A is much more symmetric with respect to the platinated lesion than that of HMGB 1 domain A. Furthermore, HMGB4 presented stronger repair inhibition capacity than HMGB1 at an equimolar concentration. These results support the hypothesis that HMGB4 enhances cisplatin cytotoxicity in TGCT. Chapter 5 will be the conclusion chapter of this thesis. Works in this thesis will be summarized with what we can learn from those results. In additions, future directions in the study of HMGB proteins will be suggested. Appendices A and B describe the incomplete work on HMGB4 in live cells. Appendix A delineates the expression profile of human HMGB4 established by western blot analysis. Human HMGB4 presented a testis-preferred expression. In Appendix B, attempts to establish a HMGB4 knockdown testicular cancer cell line are described.
by Semi Park.
Ph.D.in Inorganic chemistry

APA, Harvard, Vancouver, ISO, and other styles

16

Bharath, M. M. Srinivas. "Towards The Understanding Of The Structural Biology Of Histone H1." Thesis, Indian Institute of Science, 2000. http://hdl.handle.net/2005/167.

Full text

Abstract:

In the eukaryotic nucleus, an immense length of DNA is compactly packaged to generate an ordered three-dimensional hierarchical structure called chromatin (van Holde, 1988; Wolffe, A.P, 1998). This organization forms a template for various DNA transaction processes like replication, transcription, recombination etc. The different stages of organization of the chromatin finally results in the 10,000-fold compaction observed in the metaphase chromosome. The problem of how the fibres of chromatin are folded has interested biologists and biochemists for decades. It has long been recognized that the Histones play a major part in this folding. However, the distinctly different roles of the Histones H2A, H2B, H3 and H4 on one hand and the lysine rich Histones such as Histone H1 and its cognates on the other, were not understood until after the discovery of the nucleosomes in the early 1970s. Some of the early insights into the structure of chromatin came through the digestion of nuclear chromatin with calcium-dependent endonucleases like micrococcal nuclease. A repeating kinetic intermediate of about 200 bp of DNA with Histones was obtained (Simpson, 1978). Based on repeating pattern of micrococcal nuclease digested chromatin and structural studies, Kornberg (1974) proposed that chromatin is composed of a flexible chain of repeating units of 100 A0 diameter. These units were termed as "nucleosomes" (Oudet et al, 1975). It then became clear that the Histones H2A, H2B, H3 and H4 were constituents of the nucleosome core particle whereas the lysine rich Histone H1 was somehow associated with the linker DNA between core particles. Hence, the formers are called core Histones and the latter as linker Histones. On further digestion of nucleosome, a nucleosome core was obtained in which wrapping of 146 bp of DNA about the Histone octamer to form the core particle provided the first level of folding. Electron microscopy and X-ray diffraction techniques suggested that this particle is a disk, 57 A0 thick and 110 A0 in diameter, and that the DNA is wound around the Histone core (Finch et al, 1977), But this cannot account for the many thousand-fold condensation of the DNA in the eukaryotic nucleus. The "string of beads" structure observed obviously could not satisfy the compaction requirement. It soon became evident that there exists some level of higher order folding of the chromatin fiber. In a classical paper, Finch and Klug (1976), showed that the extended nucleosomal filaments condense into irregular fibers of about 30 nm diameter in the presence of low concentrations of Mg 2+. Based on the data from earlier structural studies, these authors proposed a solenoid model in which nucleosomes were wrapped into a regular helix with a pitch of about 11nm. Later, it was observed that the formation of well defined fibers requires the presence of lysine rich Histones such as Histone H1.

APA, Harvard, Vancouver, ISO, and other styles

17

Lucey, Michelle M. "The expression of the High Mobility Group N (HMGN) family of proteins during development of the mouse eye." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 120 p, 2008. http://proquest.umi.com/pqdweb?did=1597629771&sid=19&Fmt=2&clientId=8331&RQT=309&VName=PQD.

Full text

APA, Harvard, Vancouver, ISO, and other styles

18

Mohan, Gokula. "Chromatin-binding HMGN proteins and the neuronal differentiation of enbryonal carcinoma cells in vitro." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3316/.

Full text

Abstract:

Embryonic stem (ES) cells are able to differentiate in vitro into endodermal, mesodermal and ectodermal cell types. ES cells and their close counterparts, embryonic carcinoma (EC) cells, are a useful model system for studying the mechanisms governing neuronal differentiation. Since High Mobility Group-nucleosome binding (HMGN) genes are regulated in a developmental-stage specific manner during mouse embryogenesis and cellular differentiation, their roles in undifferentiated and neural differentiating P19 EC cells were examined. Work presented in this thesis firstly optimises the Retinoic Acid (RA) -induced neural differentiation protocol of P19 EC cells based on key neuronal and glia markers. Two crucial steps of RA concentration and cell plating density were shown to increase the efficiency of neuronal differentiation. Analysis of HMGN proteins showed they were ubiquitously expressed in undifferentiated and neural differentiating P19 cells. HMGN2 and HMGN3 were up-regulated while HMGN1 remained unchanged upon neural commitment. Unusually, HMGN3 protein was localised in the cytoplasm of P19 cells. To study the possible role of HMGN proteins, HMGN1 and HMGN2 were knocked down using siRNAs. HMGN1 and HMGN2 knockdown in undifferentiated P19 EC cells dramatically down-regulated the key pluripotency regulator genes Oct4, Nanog and Sox2. Furthermore, HMGN1 and HMGN2 knockdown in neural differentiating cells affected seven neuron-specific genes. These data suggest that HMGN proteins may play roles in regulating genes that are involved in maintaining pluripotency and regulating neural differentiation in P19 cells.

APA, Harvard, Vancouver, ISO, and other styles

19

Shearer, Alexander Glennon. "HMG-CoA reductase : protein regulation by a quality control pathway /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2004. http://wwwlib.umi.com/cr/ucsd/fullcit?p3144341.

Full text

APA, Harvard, Vancouver, ISO, and other styles

20

Bonne-Andrea, Catherine. "Contribution à l'étude des propriétés et du rôle biologique de la protéine non-histone HMG1." Paris 6, 1986. http://www.theses.fr/1986PA066451.

Full text

APA, Harvard, Vancouver, ISO, and other styles

21

Elashry, Abd-elNasser. "Two C. elegans high mobility group genes, hmg-12 and hmg-1.1, function in neural postembryonic development and cell survival." Doctoral thesis, [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972602518.

Full text

APA, Harvard, Vancouver, ISO, and other styles

22

Natarajan, Suchitra. "Roles of high mobility group AT-hook protein 2 (HMGA2) in human cancers." Elsevier, 2013. http://hdl.handle.net/1993/31092.

Full text

Abstract:

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

APA, Harvard, Vancouver, ISO, and other styles

23

McA'Nulty, Megan Moore. "Cisplatin in yeast--repair of DNA adducts and binding of HMG domain proteins." Thesis, Massachusetts Institute of Technology, 1995. http://hdl.handle.net/1721.1/32176.

Full text

APA, Harvard, Vancouver, ISO, and other styles

24

Denbow, Cynthia J. "Membrane Domain of Plant 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase: Targeting, Topology, and Function." Diss., Virginia Tech, 1997. http://hdl.handle.net/10919/30472.

Full text

Abstract:

The rate limiting step in isoprenoid biosynthesis is catalyzed by 3-hydroxy-3-methylglutaryl CoA reductase (HMGR, EC 1.1.1.34). In plants, HMGR is encoded by small gene families whose members are differentially expressed. In tomato, hmg2 was previously isolated and sequenced. We report the isolation and sequence analysis of a clone (pCD4) encompassing exon I of tomato hmg1 which encodes the putative membrane domain. Sequence comparisons of plant HMGR proteins reveal two hydrophobic stretches within the amino terminus which are highly conserved among species. Using in vitro transcription and translation systems, the membrane domain structure of two tomato HMGR isoforms, HMG1 and HMG2, were analyzed. Results from these experiments reveal that tomato HMGRs are targeted to microsomal membranes in a cotranslational fashion that does not involve cleavage of an N-terminal targeting peptide. Membrane topography of HMGR was revealed by protease protection studies, indicating that both tomato HMGRs span the membrane two times such that both the C- and N-termini are located within the cytosol. HMG2 but not HMG1 was glycosylated in the in vitro system. Deletion of the hmg1 5' untranslated regions and sequences encoding the first six highly charged amino acids resulted in inefficient translation in vitro. However, targeting to microsomes was unchanged. HMG1 membrane domain was tagged with a FLAG epitope to facilitate in vivo studies. Agrobacterium-mediated transformation was used to introduce the tagged hmg1 gene into two Nicotiana tabacum cell lines, BY-2 and KY-14. The slow growth kinetics of KY-14 prevented effective recovery of transformed lines, however, Northern analyses of BY-2 showed that the hmg1 transgene was expressed. Comparisons of BY-2 and KY-14 revealed differences in defense responses to elicitor treatment. BY-2 cells showed minimal defense capabilities, whereas KY-14 cells were rapidly induced as indicated by increased HMGR enzyme activity and browning of the cells. HMGR enzyme activity was decreased in both KY-14 and BY-2 cells following sterol treatment, but the reduction was more pronounced in KY-14 cells. Thus transgenic BY-2 cells may be useful in future in vivo immunolocalization studies, but analyses of HMGR transcriptional regulation and regulated degradation will require use of the more responsive KY-14 cells..
Ph. D.

APA, Harvard, Vancouver, ISO, and other styles

25

Roemer, Sarah Clark. "Structural and functional analysis of progesterone receptor-DNA interaction /." Connect to full text via ProQuest. IP filtered, 2005.

Find full text

Abstract:

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;

APA, Harvard, Vancouver, ISO, and other styles

26

Ronfani, Lorenza. "Cloning and knock-out of the mouse gene coding for the high mobility group 2 protein (HMG2)." Thesis, Open University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342940.

Full text

APA, Harvard, Vancouver, ISO, and other styles

27

Sparkes, Andrew Charles. "The isolation and characterisation of Sry-related HMG box gene from Droposhila melanogaster." Thesis, University of Portsmouth, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310391.

Full text

APA, Harvard, Vancouver, ISO, and other styles

28

Gupta, R. "Isolation, characterisation and expression of genes encoding plant high mobility group HMG-I/Y proteins." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599793.

Full text

Abstract:

The aim of the present study was to isolate gene(s) encoding HMG-I/Y proteins from higher plants and study the regulation of their expression. In order to isolate an HMG-I/Y gene a pea genomic library was screened with a pea HMG-I/Y cDNA resulting in the isolation of three different chimeric clones containing only the 3' end of the HMG-I/Y gene. The coding region (with a single intron of 201 bp) of the pea HMG-I/Y gene was isolated as a 795 bp fragment by PCR on genomic DNA. Several attempts using different approaches to isolate the promoter region of the pea HMG-I/Y gene were unsuccessful. The MHG-I/Y gene was present in a single-copy and expressed in all organs as determined by Southern and northern blot analysis. A cDNA encoding the HMG-I/Y protein from Arabidopsis thaliana was sequenced and characterised. The 903 bp cDNA encodes an HMG-I/Y protein of 204 amino acid residues with a calculated molecular mass of 22 kDa containing 4 copies of the 'AT-hook' motif. Southern blot analysis on Arabidopsis genomic DNA revealed the presence of a single copy of the HMG-I/Y gene. The HMG-I/Y gene was located near the top of chromosome 1 by RFLP analysis of F₈ recombinant inbred lines. Northern blot analysis demonstrated the expression of the HMG-I/Y gene in all organs of Arabidopsis examined with the highest expression in flowers and developing siliques. A genomic clone encoding the HMG-I/Y protein was isolated from an Arabidopsis genomic library using the HMG-I/Y cDNA as a probe. A 6.3 kb genomic fragment was sequenced and includes the coding region (with a single 73 bp intron) of the HMG-I/Y gene and 5209 bp of 5' upstream sequence and 412 bp of 3' downstream sequence.

APA, Harvard, Vancouver, ISO, and other styles

29

Menezes, Amanda Caroline Cardoso Corrêa Carlos. "Efeito do hidrolisado proteico do grão de amaranto (Amaranthus cruentes L. BRS Alegria) processado na solubilização micelar do colesterol e na ação da HMGR." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/6/6138/tde-16102017-094758/.

Full text

Abstract:

Introdução: A obesidade e a dislipidemia são grandes contribuintes dos agravos cardiovasculares. O consumo de vegetais, principalmente de suas proteínas, atua de forma protetora na magnitude destes agravos. Há grandes indícios de que a proteína do amaranto possui efeito hipocolesterolemizante pela ação de peptídeos, originários de sua digestão incompleta. Objetivo: Verificar a ação, in vitro, do hidrolisado proteico do amaranto, submetido a diferentes processamentos, na solubilização micelar do colesterol e inibição da atividade enzimática HMGR. Métodos: As farinhas processadas e crua foram analisadas quanto seu teor de aminoácidos. Os isolados proteicos das farinhas do grão de amaranto tostado, extrusado e cru, foram submetidos à hidrólise enzimática e em seguida, foi elaborada uma solução de sais biliares e colesterol para avaliar a capacidade dos hidrolisados proteicos em diminuir a solubilização micelar de colesterol. Utilizaram-se os ultra filtrados (PM menor que 3 kDa) em concentração de 3 mg/mL em equivalentes de albumina, e para os de peso moleculares maiores foram utilizados 10 mg/mL. Com o intuito de verificar o mecanismo de inibição da síntese endógena de colesterol, somente, foram utilizados os hidrolisados ultra filtrados. Nos ensaios de inibição enzimática da HMGR foram utilizadas concentrações de hidrolisados (0,1, 0,5 e 1 mg/mL) para avaliar a inibição e comparar a pravastatina (inibidor conhecido). Resultados: A composição de aminoácidos demonstrou-se adequada, quando comparada a recomendação de aminoácidos essenciais para crianças de 2 a 5 anos. Os aminoácidos hidrofóbicos constituem 30 por cento do total de aminoácidos. Ao avaliar o efeito do hidrolisado na solubilização micelar do colesterol, foi observado que houve diferença (p < 0,004) devido ao processamento. O hidrolisado proteico da farinha crua (IPHc), com peptídeos de peso molecular maior que 3 kDa, reduziu a solubilização micelar do colesterol em 44,09 ± 1,5 por cento , enquanto que os hidrolisados de farinha tostada (IPHt) e extrusada (IPHe) reduziram em 31,24 ± 5,9 por cento e 24,97 ± 4,1 por cento . Já os hidrolisados com peso molecular menor que 3 kDa apresentaram pouca diferença (p < 0,03) em relação ao processamento. A redução da solubilidade micelar observada pelos IPHc e IPHe foi semelhante: 37,21 ± 1,65 por cento e 35,45 ± 0,4 por cento , respectivamente. O IPHt apresentou a menor redução de 22,47 ± 4,6 por cento . Os hidrolisados da farinha de amaranto também foram capazes de inibir a atividade da enzima HMGR em diversas concentrações. O controle da atividade normal da enzima apresentou 0,65 ± 0,05 µmol de NAPH oxidada min/mg equivalente de albumina. O IPHc, em concentrações de 0,1 e 0,5 mg/mL, apresentou efeito similar ao da pravastatina, diferindo do controle (p < 0,05), produzindo: 0,24 ± 0,03 e 0,29 ± 0,13 de µmol de NAPH oxidada min/mg equivalente de albumina. Por outro lado o IPHt apresentou efeito similar ao da pravastatina em concentração superior ao cru; em 1 mg/mL produziu 0,20 ± 0,09 de µmol de NAPH oxidada min/mg equivalente de albumina. O IPHe apresentou efeito inibidor da enzima em concentração de 0,1 mg/mL, porém menor do que o observado para a pravastatina. Conclusões: A proteína do grão de amaranto hidrolisada possui indícios de atividade hipocolesterolêmica. Sendo capaz de atuar tanto na via exógena quanto na via endógena, inibindo a absorção do colesterol e sua síntese de forma indireta. O processamento térmico diminuiu esta capacidade, mas ainda demonstra resultados significativos. Dentre os processamentos, a extrusão mostrou ter diminuído este efeito, embora os seus resultados possam ter sido influenciados pela quantidade de componentes no isolado proteico, como lipídeos e compostos fenólicos.
Introduction: Obesity and dyslipidemia are major contributors of cardiovascular diseases. The consumption of vegetables, especially their protein, acts protectively on the magnitude of these injuries. There is evidence that amaranth protein has a cholesterol-lowering effect by the action of peptides originating from its incomplete digestion. Objective: To assess the effect, in vitro, of the hydrolyzed protein of amaranth, submitted to different processes, on the reduction of the micellar solubilization of cholesterol and on the inhibition of HMGR enzyme activity. Methods: The raw and processed flours were analyzed for their content of amino acids. The isolated protein from amaranth grain flour toasted, extruded and raw, were subjected to enzymatic hydrolysis. Subsequently, it was prepared a solution of bile salts and cholesterol to assess the ability of the hydrolyzed protein to decrease the micellar solubilization of cholesterol. It was used the ultra-filtered peptides (MW up to 3 kDa) at concentration of 3 mg/mL equivalent albumin; and for higher molecular weights, it was used 10 mg/mL. In order to verify the mechanism of inhibition of the cholesterol endogenous synthesis, only it was used the hydrolyzed ultra-filtered peptides with MW < 3 KDa. In the assays of HMGR inhibition, several concentrations of peptides were used (0.1, 0.5 and 1 mg/mL) to compare the inhibition to pravastatin (a known inhibitor). Results: The amino acid composition showed to be adequate when compared to the recommendation of essential amino acids for children 2-5 years. Hydrophobic amino acids compose 30 per cent in total amino acids. When evaluating the effect of the hydrolyzate micellar solubilization of cholesterol has been observed that significant difference (p <0.004) from the processing. The peptides from raw flour hydrolyzed protein (IPHc) with a molecular weight greater than 3 kDa reduced micellar solubilization of cholesterol by 44.09 ± 1.5 per cent , while those from the roasted flour (IPHt) and extruded flour (IPHe) reduced by 31.24 ± 5.9 per cent and 24.97 ± 4.1 per cent . Peptides with a molecular weight up to 3 kDa showed little difference (p < 0.03) due to processing. The reduction of the observed micellar solubility of IPHc and IPHe were similar: 37.21 ± 0.4 per cent and 35.45 ± 1.65 per cent , respectively. The IPHt showed the smallest decrease of 22.47 ± 4.6 per cent . The peptides from amaranth flour were also able to inhibit the activity of the enzyme HMGR in various concentrations. The control of normal enzyme activity showed 0.65 ± 0.05 mol of NAPH oxidized min/mg equivalent of albumin. The IPHc at concentrations of 0.1 and 0.5 mg/mL had an effect similar to that of pravastatin, different from control (p < 0.05), yielding: 0.24 ± 0.03 and 0.29 ± 0.13 mol of the NAPH oxidized min/mg equivalent of albumin. On the other hand, IPHt showed a similar effect to higher concentration of pravastatin in the raw, and in 1 mg/mL produced from 0.20 ± 0.09 mol of oxidized NAPH min/mg equivalent of albumin. The IPHe showed the inhibitory effect on the enzyme concentration as lower as 0.1 mg/mL, but less pronounced than pravastatin. Conclusions: The peptides from hydrolysis of amaranth grain has evidence of hypocholesterolemic activity. They are able to act both in exogenously and endogenous pathways, inhibiting the absorption of cholesterol and its synthesis. The thermal processing reduces this capacity, but still shows significant results. Among the processing, extrusion deserves less attention than other one, although their results may have been influenced by the amount of the isolated protein components, such as lipids and phenolic compounds.

APA, Harvard, Vancouver, ISO, and other styles

30

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 text

Abstract:

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.

APA, Harvard, Vancouver, ISO, and other styles

31

Shinn, Annie Heekyung. "Evaluating the effects of HMG -CoA reductase inhibitors on C -reactive protein, butyrylcholinesterase, and lipids." Scholarly Commons, 2004. https://scholarlycommons.pacific.edu/uop_etds/2675.

Full text

Abstract:

The objectives of this two part prospective study were to evaluate the effects of statins on C-reactive protein (CRP), butyrylcholinesterase (BChE), lipids, and the relationships between these parameters. Subjects enrolled in this study were separated into two cohorts. The first group (study 1) consisted of 37 subjects converted from pravastatin to cerivastatin. The second group (study 2) consisted of 11 subjects with diabetes initiated on cerivastatin therapy. The subjects were followed for 12-weeks in the Lipid Clinic at David Grant Medical Center at Travis Air Force Base. CRP, BChE, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) were measured at baseline, 6-weeks, and 12-weeks. In study 1, CRP (p = 0.704) and BChE (p = 0.746) remained relatively stable over 12-weeks. The lipid panel changed significantly with TC (p < 0.001) and LDL (p < 0.001) decreasing and HDL (p = 0.017) increasing. Although TG declined numerically, it was not statistically significant (p = 0.649). A significant negative correlation was detected at baseline (r = −0.353, p = 0.032), but lost at 6-weeks and 12-weeks. In study 2, CRP declined by 42.9%, but was not statistically significant (p = 0.178). BChE remained relatively stable over 12-weeks (p = 0.666). TC (p < 0.001) and LDL (p < 0.001) declined and TG (p = 0.035) fluctuated over the course of the study. HDL increased, but it was not statistically significant (p = 0.396). Significant positive correlations were seen between CRP and TG (r = 0.908, p < 0.001) and BChE and TC (r = 0.721, P = 0.012) at baseline and BChE and TG (r = 0.64, p = 0.034) at 12-weeks. These results suggest that statin effects on CRP are independent of the lipid-lowering effects and switching statins may not affect CRP disposition. Cerivastatin does not appear to have effects on BChE activity. Lastly, a possible competitive relationship may exist between CRP and BChE. This is suggested by the negative correlation seen in study 1 and with the gain in correlation between BChE and TG as the correlation was lost between CRP and TG in study 2.

APA, Harvard, Vancouver, ISO, and other styles

32

Schlüter, Claudia. "Untersuchungen zur Bedeutung ausgewählter HMG-Proteine bei der Differenzierung und Proliferation von Endothel- und glatten Muskelzellen." kostenfrei, 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975431765.

Full text

APA, Harvard, Vancouver, ISO, and other styles

33

Canaple, Laurence. "Structure et fonction du gene dspi codant pour une proteine a boites hmg chez drosophila melanogaster." Orléans, 1997. http://www.theses.fr/1997ORLE2031.

Full text

Abstract:

Les proteines hmg 1/2 sont des nucleoproteines non histones tres abondantes. Les proteines hmg1 et hmg2 de vertebres contiennent deux domaines de fixation a l'adn, appeles boites hmg a et b et une region c-terminale acide. Leur activite biologique n'est pas bien definie mais leur ubiquite et leur abondance suggerent un role cellulaire important. Au laboratoire, nous nous interessons a une proteine hmg de drosophile, dsp1. Cette proteine convertit la proteine dorsal d'activateur transcriptionel en represseur. Dans un premier temps, nous avons determine l'organisation structurale du gene dsp1. Localise sur le chromosome x en position 14 cd, il est constitue de 7 exons et de 6 introns. Nous mettons en evidence qu'un epissage alternatif dans la region 5' non traduite et dans la sequence codante conduit a la formation de deux proteines isoformes. Ces proteines contiennent une region riche en glutamine et un domaine hmg, compose de deux boites hmg et d'une queue acide. La conservation de l'organisation des jonctions exons/introns entre le gene dsp1 et les genes hmg1/2 de vertebres et la forte homologie entre les proteines dsp1 et hmg1/2 suggerent que les genes dsp1 et hmg1/2 sont issus d'un meme gene ancestral. Nous montrons ensuite qu'au cours de l'ovogenese, la proteine dsp1 est synthetisee par les cellules nourricieres de la chambre ovarienne. Environ deux heures apres la fecondation, nous observons une expression zygotique du gene dsp1. La proteine dsp1 adopte alors un profil d'expression ubiquitaire et exclusivement nucleaire. Chez l'adulte, l'expression de dsp1 se limite essentiellement aux ovaires et au systeme nerveux central. Afin de preciser la fonction de la proteine dsp1, nous avons, dans un troisieme temps, etudie l'interaction entre les proteines dorsal et dsp1. Nous montrons qu'une interaction de nature proteique existe in vitro entre ces deux proteines.

APA, Harvard, Vancouver, ISO, and other styles

34

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.

Full text

APA, Harvard, Vancouver, ISO, and other styles

35

OHYAMA, YUMIKO. "Etude par resonance magnetique nucleaire 2d et 3d de la structure tridimensionnelle de la boite a de la proteine hmg1." Paris 6, 1996. http://www.theses.fr/1996PA066309.

Full text

Abstract:

La structure tridimensionnelle de la boite a de la proteine hmg1 de mammiferes (rat) a ete determinee par resonance magnetique nucleaire (rmn) et modelisation moleculaire. Cette proteine appartient a la serie des nucleoproteines appelees high mobility group proteins qui sont caracterisees par leur complexation avec l'adn. Les proteines hmg1 et ses homologues possedent deux regions basiques bien structurees d'environ 80 residus: domaines n-terminal et central. Ils sont appeles respectivement boites a et b qui se complexent sans specificite sequentielle avec les adn courbes et distordus. Avec des contraintes obtenues a partir des experiences rmn homonucleaires et heteronucleaires 2d et 3d, nous avons construit des modeles par le logiciel xplor. Les structures obtenues ont une forme en l comme celles des autres proteines hmg. Le bras long est constitue de la region n-terminale (residus 2-14) et de la troisieme helice (residus 53-76) qui sont accolees l'une contre l'autre, tandis que le bras court contient la premiere (residus 15-29) et la deuxieme helice (residus 40-50). La disposition du l est vrillee au niveau du coude entre les bras long et court. A cet emplacement, il existe un cluster hydrophobe, dans lequel les cycles aromatiques des residus phe forment entre eux un angle voisin de 60. Cette disposition pourrait etre liee a une modification structurale au moment de l'interaction avec l'adn. Certaines differences ont ete observees entre la proteine native et la proteine mutee etudiee par une equipe anglaise. D'abord, la forme en l est differente: pour la proteine native, le bras long est incurve, car la partie n-terminale etant plus proche de l'helice h3, les interactions entre h3 et le debut de l'helice h1 responsables de cette courbure sont plus importantes que dans le cas de la proteine mutee. Ces interactions pourraient stabiliser la forme de la molecule. Le bras court est egalement plus elargi pour la boite a native que pour la boite mutee. Ceci est du a l'encombrement sterique des cycles de his 26, his 30 et phe 40 a l'interieur du bras court. La difference structurale constatee entre les boites a et b est localisee au niveau de la region n-terminale et de l'helice h1 considerees comme le site d'interaction n'ayant pas la meme forme, ce qui peut etre a l'origine d'une difference de mode d'interaction avec l'adn. La boite a qui se complexe preferentiellement avec l'adn cruciforme (croisement statique), tandis que la boite b et son extension avec la partie c-terminale se complexent avec l'adn sur-enroule (croisement dynamique). En conclusion, la rmn a permis d'etablir un modele de structure 3d de la boite a native de hmg1, de le comparer a la boite a mutee ainsi qu'a la boite b et de constituer ainsi une base pour des etudes ulterieures d'interaction avec l'adn

APA, Harvard, Vancouver, ISO, and other styles

36

Suraty, Thaís Rezende. "Efeito da proteína de amaranto (Amaranthus cruentus L. BRS Alegria) na atividade enzimática hepática da HMG-CoA redutase e seu papel no metabolismo lipídico em hamsters." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/89/89131/tde-29062015-170422/.

Full text

Abstract:

Introdução: Atualmente as Doenças Crônicas não Transmissíveis (DCNTs) são um dos maiores problemas de saúde pública da sociedade. É bastante claro o papel da dieta no controle do colesterol e na incidência de doenças cardiovasculares. Neste sentido, o amaranto desperta grande interesse devido a sua propriedade hipocolesterolemizante. Estudos sugerem que seu efeito hipocolesterolemizante está associado à inibição da enzima HMG-CoA redutase, chave na síntese do colesterol endógeno. Objetivo: Avaliar a atividade enzimática hepática da HMG-CoA redutase de hamsters alimentados com proteína de amaranto. Metodologia: Trinta hamsters foram divididos em 5 grupos e receberam dieta diferenciadas pela fonte protéica. Os grupos I e Icol receberam dieta com 20% de proteína de amaranto e os grupos caseína C e Ccol receberam dieta com 20% de caseína. Os grupos \"col\" apresentavam dieta com 0,1% de colesterol e 13,5% de gordura de coco. O metabolismo lipídico foi acompanhado através do monitoramento das concentrações plasmáticas de colesterol total, triacilgliceróis, HDL, e fração não-HDL nos animais. A excreção de colesterol e ácidos biliares foram quantificados nas fezes dos animais e o grau de esteatose hepática foi determinada através de análises histológicas do lobo direito do fígado. A atividade da enzima HMGR nos fígados foi medida por meio do Kit CS 1090 da Sigma-Aldrich com adaptações segundo Cong et al, 2012. A análise é baseada em espectrometria com absorbância de 340nm a 37ºC, que representa a oxidação de NADPH pela HMG-CoA redutase, na presença do substrato HMG-CoA. Conclusões: A proteína de amaranto pode ser considerado um aliado na redução dos agravos gerados pela dislipidemia, uma vez que reduziu significativamente os níveis de colesterol plasmático e gordura hepática, além de ser demonstrado seu efeito na redução da atividade da enzima HMG-CoA redutase dos animais hipercolesterolemizados que se alimentaram com proteína de amaranto. Uma vez verificado o efeito hipocolesterolemizante e seu possível mecanismo de ação por meio da enzima HMG-CoA redutase, espera-se com isso, estimular o consumo pela população brasileira produção de amaranto no Brasil, como alternativa para diversificar a dieta e a agricultura.
Introduction: Nowadays, Non-Communicable Chronic Diseases (NCCD) are a major challenge in health public. It is evident the role of diet in the control of cholesterol and incidence of cardiovascular disease. In this sense, amaranth arouses great interest due to its hypocholesterolemic property. Studies suggest that amaranth\'s hypocholesterolemic effect is associated with the inhibition of the enzyme HMG-CoA reductase, known as the key process to the endogenous cholesterol synthesis. Objective: Evaluate the hepatic enzymatic activity of HMG-CoA reductase in hamsters fed with amaranth protein. Methodology: Amaranth protein was isolated according to the conventional isoelectric precipitation methodology. Thirty hamsters were divided in 5 groups and were fed diets with different protein source. Experimental groups (I and lcol) had a diet containing 20% of protein amaranth and control groups(C and Cool) received a diet with 20% of casein. Moreover, groups \"col\" had also a diet with 0.1% cholesterol and 13.5% coconut oil in their composition. The lipid metabolism was accompanied through monitoring of plasma concentrations of total cholesterol, triglycerides, HDL and non-HDL fraction in animals. Excretion of cholesterol and bile acids were quantified in the feces of animals and the degree of hepatic steatosis was determined by histological analysis of the liver\'s right lobe. The HMGR enzyme activity in the liver was measured by the CS 1090 Kit from Sigma-Aldrich adjusted in accordance with Cong et al, 2012. The analysis is based on spectrometry with absorbance of 340nm at 37 ° C, which represents the oxidation of NADPH by HMG-CoA reductase in the presence of HMG-CoA substrate. Conclusions: Amaranth protein can be considered as an ally in reducing of injuries generated by dyslipidemia, since it significantly reduced levels of plasma cholesterol and hepatic fat. Furthermore, it was demonstrated its effect on reducing activity of HMG-CoA reductase enzyme in hypercholesterolemic animals, which were fed with amaranth protein. Therefore, once verified the hypocholesterolemic effect of amaranth and its possible action mechanism through HMG-CoA reductase enzyme, stimuli on the production of amaranth are expected as an alternative to diversify the diet and agriculture.

APA, Harvard, Vancouver, ISO, and other styles

37

Milner, Michael James. "Isolation and characterisation of genes encoding HMG domain proteins from Coprinus cinereus and an analysis of their role in mating." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365718.

Full text

APA, Harvard, Vancouver, ISO, and other styles

38

Rittenhouse, Kimberley Rochelle. "Bullwinkle, an HMG box protein, is required for proper development during oogenesis, embryogenesis and metamorphosis in Drosophila melanogaster /." Thesis, Connect to this title online; UW restricted, 1996. http://hdl.handle.net/1773/10267.

Full text

APA, Harvard, Vancouver, ISO, and other styles

39

Bounaix, Morand du Puch Christophe. "Analyse des interactions ADN lésé / protéines : Optimisations méthodologiques et applications aux dommages de l’ADN engendrés par les dérivés du platine." Grenoble, 2010. https://theses.hal.science/tel-00549987.

Full text

Abstract:

La présence de lésions sur l'ADN contribue à déstabiliser sa structure, bloquant certains processus vitaux pour la cellule. Ces altérations peuvent cependant avoir un intérêt thérapeutique, par exemple dans le cas de l'utilisation d'anticancéreux tels que les dérivés du platine. Les adduits volumineux qu'ils génèrent, s'ils ne sont pas réparés, entraînent la cellule vers l'apoptose. La compréhension de la réponse à ces anticancéreux passe par l'étude des protéines qui interagissent directement avec les dommages, et dont l'ensemble constitue l'interactome des lésions de l'ADN. Ce travail de thèse présente le développement d'outils destinés à compléter la liste des protéines associées aux adduits du platine. Dans un premier temps, nous avons utilisé un piège à protéines (ligand fishing) constitué de plasmides lésés fixés sur des billes magnétiques. Trois dérivés du platine ont été sélectionnés pour générer les lésions : le cisplatine (molécule princeps), l'oxaliplatine, et le satraplatine. Ce piège a permis d'obtenir, à partir d'extraits nucléaires issus de cellules cancéreuses HeLa et grâce à une identification par protéomique, une liste de candidats comprenant des protéines déjà connues (HMGB1, hUBF, complexe FACT), mais aussi 29 nouveaux membres de l'interactome. Parmi ceux-ci, nous avons relevé PNUTS, TOX4 et WDR82, qui constituent les sous-unités du complexe PTW/PP, très récemment découvert. La présence de ce complexe a été également validée sur un modèle d'adénocarcinome mammaire MDA MB 231, et les conséquences biologiques de son interaction avec les adduits du platine devront maintenant être précisées. Dans un second temps, nous avons mis au point une biopuce permettant d'étudier les interactions ADN lésé/protéine par SPRi. Les affinités respectives d'HMGB1 et du nouveau candidat TOX4 pour les adduits des trois dérivés du platine ont pu être ainsi confirmées. Dans un dernier temps, nous avons étudié le rôle de DDB2 (acteur de la reconnaissance des photoproduits UV) dans la prise en charge des adduits platinés. Les expérimentations menées sur les cellules MDA MB 231 exprimant DDB2 de façon différentielle nous ont permis de vérifier que cette protéine ne participe pas à la réparation des adduits du cisplatine, contribuant plutôt à potentialiser l'action cytotoxique de cet agent. Dans le futur, nos microsystèmes pourront être adaptés à l'étude de l'interactome d'autres lésions de l'ADN
DNA lesions contribute to the alteration of DNA structure, thereby inhibiting essential cellular processes. Such alterations may be beneficial for chemotherapies, for example in the case of platinum anticancer agents. They generate bulky adducts that, if not repaired, ultimately cause apoptosis. A better understanding of the biological response to such molecules can be obtained through the study of proteins that directly interact with the damages. These proteins constitute the DNA lesions interactome. This thesis presents the development of tools aiming at increasing the list of platinum adduct-associated proteins. Firstly, we designed a ligand fishing system made of damaged plasmids immobilized onto magnetic beads. Three platinum drugs were selected for our study: cisplatin, oxaliplatin and satraplatin. Following exposure of the trap to nuclear extracts from HeLa cancer cells and identification of retained proteins by proteomics, we obtained already known candidates (HMGB1, hUBF, FACT complex) but also 29 new members of the platinated-DNA interactome. Among them, we noted the presence of PNUTS, TOX4 and WDR82, which associate to form the recently-discovered PTW/PP complex. Their capture was then confirmed with a second model, namely breast cancer cell line MDA MB 231, and the biological consequences of such an interaction now need to be elucidated. Secondly, we adapted a SPRi biochip to the study of platinum-damaged DNA/proteins interactions. Affinity of HMGB1 and newly characterized TOX4 for adducts generated by our three platinum drugs could be validated thanks to the biochip. Finally, we used our tools, as well as analytical chemistry and biochemistry methods, to evaluate the role of DDB2 (a factor involved in the recognition of UV-induced lesions) in the repair of cisplatin adducts. Our experiments using MDA MB 231 cells differentially expressing DDB2 showed that this protein is not responsible for the repair of platinum damages. Instead, it appears to act as a positive mediator of their cytotoxicity. In the near future, the abovementioned microsystems will be adapted to the study of the interactome of other DNA lesions

APA, Harvard, Vancouver, ISO, and other styles

40

Arce, Cerezo Altamira. "Study of the role of the overexpression of the high mobility group-AT-hook-1 (HMGA1) protein in the adipose tissue and its implications in the development of obesity and insulin resistance." Doctoral thesis, Universitat Autònoma de Barcelona, 2013. http://hdl.handle.net/10803/126522.

Full text

Abstract:

La obesidad es un trastorno metabólico complejo que ha alcanzado proporciones epidémicas en los países desarrollados y en desarrollo. Por otra parte, la obesidad es un factor de riesgo importante que a su vez aumenta el riesgo de desarrollar otras enfermedades tales como la resistencia a la insulina, diabetes tipo 2 y enfermedades cardiovasculares. El conocimiento de las causas y mecanismos que desencadenan el desarrollo de estas enfermedades es de vital importancia para su prevención y tratamiento. Sin embargo, los mecanismos por los que la obesidad se origina, desarrolla y predispone a otras complicaciones metabólicas no se entienden completamente. El desarrollo de los adipocitos y de la obesidad han sido estudiados a través de diferentes modelos celulares y animales. Las proteínas “high movility-AT-hook-Group-1” (HMGA1) han sido implicados en ambos procesos, aunque se desconoce su función concreta. Para ello, en este estudio hemos examinado los efectos metabólicos de HMGA1 sobreexpresión en el tejido adiposo en vivo. Para ello, hemos generado ratones transgénicos que sobreexpresan HMGA1 específicamente en el tejido adiposo. La sobreexpresión de HMGA1 en el tejido adiposo redujo la adiposidad en los ratones transgénicos. Además, estos animales eran normoglucémicos y normoinsulinémicos. Asimismo, los ratones transgénicos presentaron una mayor tasa metabólica. A pesar de la reducción de la adiposidad y de la reducción de la superficie media de los adipocitos, no se detectaron diferencias importantes en los adipocitos del tejido adiposo blanco (epWAT). Sin embargo, se detectó un proceso de remodelación activa de este depósito. Por el contrario, los animales transgénicos mostraron una menor masa de tejido adiposo y graves alteraciones morfológicas en el tejido adiposo marrón (BAT). Estos cambios implicaron la inhibición de los genes y proteínas implicados en el programa de diferenciación, biogénesis mitocondrial y la función y metabolismo de los lípidos de los adipocitos marrones, lo que llevó a la alteración de la capacidad termogénica del tejido. El estudio de la expresión de genes de epWAT y BAT de ratones transgénicos mostró la desregulación de las vías de genes implicados en el ciclo celular, ácidos grasos y el metabolismo de la insulina y la adipogénesis. Cuando se alimentaron con una dieta alta en grasas (HFD), los ratones transgénicos ganaron menos peso y mostraron menor adiposidad que los controles. Por otra parte, los ratones transgénicos mostraron una disminución del peso del epWAT y la disminución del área del adipocito. En consonancia con la falta de acumulación de grasa, lípidos y metabolitos relacionados con el metabolismo lipídico, los ratones transgénicos mostraron una reducción en los niveles de adipoquinas. En contraposición a los ratones controles que desarrollaron obesidad y resistencia a la insulina tras ser alimentados con una HFD, los ratones transgénicos ganaron menos peso y mostraron una mayor sensibilidad a la insulina. Además, los ratones transgénicos presentaron mayor infiltración de macrófagos en epWAT aunque no se observó un cambio de M2 anti-inflamatorios hacia macrófagos proinflamatorios M1. Asimismo, se observó una reducción en los niveles de citoquinas pro-inflamatorias en los ratones transgénicos, tales como IL-6, MCP-1 y TNFa, que estaban elevadas en el epWAT de los ratones controles alimentados con HFD. En resumen, estos resultados indican que la sobreexpresión de HMGA1 en el tejido adiposo altera la diferenciación terminal de los adipocitos; protegiendo a los ratones transgénicos de la obesidad inducida por la dieta grasa, de la resistencia a la insulina y de la intolerancia a la glucosa. Por tanto, este estudio sugiere que las HMGA1 podría ejercer un papel clave en la adipogénesis y en el desarrollo del tejido adiposo.
Obesity is a complex metabolic disorder that has reached epidemic proportions in both developed and developing countries. Moreover, obesity is a major risk factor that enhances the risk of developing other diseases such as insulin resistance, type 2 diabetes and cardiovascular diseases. These pathologies represent a great threat to global human health. Knowledge of the causes and mechanisms that trigger the development of these diseases is of vital importance for its prevention and treatment. However, the mechanisms through which obesity originates, develops and predisposes to other metabolic complications are not fully understood. Adipocyte and obesity development have been largely study through many cellular models. In addition, several rodent and non-rodent models have been generated for the better understanding of obesity phisiopathogenesis. As High Mobility –AT-hook- Group-1 (HMGA1) proteins have been implicated on adipogenesis in vitro, we sought to examine the metabolic effects of HMGA1 overexpression in adipose tissue in vivo. To this aim, we generated a line of transgenic mice specifically overexpressing HMGA1 in adipose tissue. Overexpression of HMGA1 in adipose tissue reduced adiposity in aP2-HMGA1 transgenic mice. In addition, these animals were normoglycaemic and normoinsulinemic. Furthermore, transgenic mice presented higher metabolic rate. Although reduced adiposity and reduced adipocyte mean area, no major differences in the adipocytes from epididymal white adipose tissue (epWAT) were detected. However, an active remodelling process was detected in this depot. In contrast, aP2-HMGA1 transgenic animals showed reduced adipose tissue mass and serious morphological alterations in brown adipose tissue (BAT). These changes implicated downregulation of genes and proteins involved in specific brown adipocyte differentiation programme, mitochondrial biogenesis and function and lipid metabolism, leading to impaired thermogenic capacity of BAT. Gene expression analysis of epWAT and BAT from transgenic mice showed dysregulation of gene pathways involved in cell cycle, fatty acid and insulin metabolism, and adipogenesis. When fed a high fat diet (HFD), transgenic mice gained less weight and showed lower adiposity than wild type littermates. Moreover, transgenic mice showed decreased epWAT weight and decreased mean adipocyte area. Consistent with the lack of fat accumulation, lipid related metabolites and adipokine secretion were reduced in transgenic mice in comparison to wild type mice. In contrast to wild-type obese and insulin resistant mice, transgenic mice remained protected against dietinduced obesity, insulin resistance and glucose intolerance. In addition, transgenic mice presented high macrophage infiltration in epWAT. Transgenic mice showed an increase in the percentage of total macrophages, although no shift from M2 anti-inflammatory to M1 proinflammatory macrophage population was observed. This was parallel to a reduction in the levels of pro-inflammatory cytokines, such as IL-6, MCP-1 and TNF-a, which were elevated in epWAT of HFD-fed wild-type mice. Taken together, these results indicate that specific HMGA1 overexpression in the adipose tissue impaired terminal differentiation of adipocytes. These effects protected transgenic mice from high fat diet-induced obesity, insulin resistance and glucose intolerance. Thus, this study suggests that HMGA1 proteins may be active players in adipogenesis and adipose tissue development, although the exact mechanism of action still remains unclear.

APA, Harvard, Vancouver, ISO, and other styles

41

BEAUJEAN, NATHALIE. "Structure de la chromatine et activite transcriptionnelle dans les embryons de souris normaux ou apres transferts de noyaux : role de la proteine hmg-i." Paris 6, 2001. http://www.theses.fr/2001PA066013.

Full text

Abstract:

Dans l'embryon de souris, la transcription zygotique ne demarre pas immediatement apres la fecondation, l'activite transcriptionnelle ne reprenant qu'a la fin du stade une-cellule. Les facteurs moleculaires responsables de cette reactivation restent a identifier, mais il est generalement admis que la structure de la chromatine serait un element regulateur cle. Les resultats obtenus au cours de ce travail de these montrent que la proteine hmg-i (proteine chromatinienne non-histone) est impliquee dans la remise en route de la transcription zygotique. Cette proteine lie selectivement les sequences riches en paires de bases da dt par l'intermediaire d'un domaine de liaison appele at-hook. Bien que presente dans les ovocytes, la proteine est absente des pronoyaux d'embryons unicellulaires juste apres leur formation et suit une cinetique de localisation nucleaire particuliere qui semble participer a la regulation temporelle de la transcription zygotique. Par ailleurs, la microinjection d'hmg-i dans des embryons unicellulaires, ainsi que la microinjection d'un peptide correspondant aux motifs at-hook, avance le demarrage de la transcription de deux heures. Cet effet activateur requiert la fixation de la proteine a l'adn et implique une modification de la structure chromatinienne, probablement par competition avec l'histone h1. Cependant, aucune indication ne permet de dire si cet effet est direct ou s'il implique le recrutement d'autres elements. J'ai montre que le degre d'acetylation de l'histone h4, qui represente un autre element regulateur de la structure chromatinienne et de la transcription au debut du developpement embryonnaire, semble connecte a la proteine hmg-i. L'etude d'un autre modele, celui du transfert de noyaux de cellules somatiques dans des ovocytes actives, suggere qu'hmg-i joue aussi probablement un role dans les remaniements de la structure de la chromatine et les changements d'activite transcriptionnelle qui accompagnent ces transferts.

APA, Harvard, Vancouver, ISO, and other styles

42

Boucher, Philippe. "Régulation nutritionnelle de l'expression des principaux gènes qui contrôlent le métabolisme et la toxicité de l'alcool et du cholestérol alimentaire : CYP2E1, LDL récepteurs, HMG CoA réductase et LRP." Lyon 1, 1999. http://www.theses.fr/1999LYO1T160.

Full text

APA, Harvard, Vancouver, ISO, and other styles

43

Slunga, Lisbeth. "Serum lipoprotein(a) in relation to ischemic heart disease and associated risk factors." Doctoral thesis, Umeå universitet, Klinisk kemi, 1993. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-101298.

Full text

Abstract:

Lipoprotein(a) (Lp(a)) consists of an LDL-like particle and the specific protein apo(a), which is very similar to plasminogen. Apo(a) contains repeated kringle structures and a serine protease domain, which cannot be activated by t-PA. Lp(a) is considered to be a predictor for atherosclerotic disease. It has been found incorporated in atherosclerotic plaques and inhibits in vitro fibrinolysis. Lp(a) was determined in 1527 randomly selected individuals participating in the Northern Sweden WHO-MONICA project. A weak but significant relation between Lp(a) and increasing age was found. Menopausal status was the strongest independent predictor of Lp(a) level in women. Fibrinogen was independently related to Lp(a) in both sexes. Only a minor fraction of Lp(a) variance could be explained for in a multiple regression model, which is in agreement with the contention that Lp(a) is highly genetically determined. Lp(a) was determined in 1571 patients investigated with coronary angiography because of suspected severe coronary artery disease (CAD). Patients with proven CAD at elective angiography had significantly higher Lp(a) than patients without significant CAD or healthy controls. Lp(a) was found to be an independent discriminator of CAD in both sexes. HLA-DR genotype 13 or 17 was found more frequently in 30 male patients with angiographic CAD at young age (< 50 years) than in 30 age matched controls. These genotypes were common in patients with high Lp(a) levels, which indicates that Lp(a) may be related to immunological processes. The reaction of Lp(a) was investigated in 32 patients with acute myocardial infarction (AMI). Lp(a) increased during the first week, but the response was comparatively weak. Individual Lp(a) responses were heterogeneous and no correlations to infarct size or changes in the acute phase proteins were found. In a randomized cross-over study on 36 hypercholesterolaemic patients treated with simvastatin/placebo during 12+12 weeks Lp(a) did not change significantly, but patients with high Lp(a) levels at baseline tended to develop further increased Lp(a). To conclude, Lp(a) was found to be an independent predictor of angiographic CAD in both men and women. Lp(a) levels are primarily genetically determined and only a small fraction of Lp(a) variance could be explained by other factors in this study. Lp(a) may be related to HLA DR types and immunological processes involved in atherosclerotic disease. Lp(a) increased slightly during the first week of AMI, but was not related to changes in the acute-phase proteins. The effective LDL-lowering agent simvastatin did not influence Lp(a) significantly.

Diss. (sammanfattning) Umeå : Umeå universitet, 1993, härtill 5 uppsatser.

digitalisering@umu

APA, Harvard, Vancouver, ISO, and other styles

44

Sterenczak, Katharina Anna [Verfasser], Jörn [Akademischer Betreuer] Bullerdiek, and Ingo [Akademischer Betreuer] Nolte. "Structural and quantitative characterisation of canine RAGE gene transcripts and evaluation of canine HMG genes and proteins for the establishment of therapeutic strategies / Katharina Anna Sterenczak. Gutachter: Jörn Bullerdiek ; Ingo Nolte. Betreuer: Jörn Bullerdiek." Bremen : Staats- und Universitätsbibliothek Bremen, 2011. http://d-nb.info/1071898140/34.

Full text

APA, Harvard, Vancouver, ISO, and other styles

45

Schmahl, Michelle Jordan. "Metabolic Profiling of Urine, Fecal, and Serum Samples and Pancreatic Tumors and Evaluation of HMGA1 Expression Levels in Pancreatic Intraepithelial Neoplasia Cells in the Ptf1a-Cre; LSL-KrasG12D Transgenic Mouse Model of Pancreatic Cancer." Miami University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=miami1523977530802748.

Full text

APA, Harvard, Vancouver, ISO, and other styles

46

Hourcade-Potelleret, Florence. "De la dose à l'effet clinique : utilisation de la modélisation dans les différentes étapes du processus de prédiction du critère clinique : Exemple avec un nouveau médicament en prévention secondaire de la morbidité-mortalité cardiovasculaire." Phd thesis, Université Jean Monnet - Saint-Etienne, 2012. http://tel.archives-ouvertes.fr/tel-00979667.

Full text

Abstract:

Les données épidémiologiques montrent une association inverse entre les taux de HDL-cholestérol (HDL-C) et le risque d'évènements cardiovasculaires. Des traitements ayant montré une augmentation significative du HDL-C, comme les inhibiteurs de la protéine de transfert des esters de cholestérol, devraient donc permettre de réduire le risque cardio-vasculaire. En utilisant différentes techniques de modélisation, nous avons tenté de quantifier l'efficacité attendue sur les événements cardiovasculaires de l'un d'entre eux, le dalcétrapib, ne disposant que de données pharmacocinétiques et pharmacodynamiques. Tout d'abord, afin d'établir la relation pharmacocinétique / pharmacodynamique entre les concentrations et la modification de HDL-C, nous avons analysé les données individuelles des patients dyslipidémiques par une approche de population. Une hausse moyenne de HDL-C de 26.4 % par rapport au placebo était alors anticipée. Nous avons ensuite tenté de corréler l'effet observé sur l'HDL-C et l'effet clinique à partir de données d'autres études par méta-régression des essais évaluant l'effet des principaux hypolipémiants en prévention secondaire. Cette modélisation n'a pas permis de montrer de corrélation entre le changement de l'HDL-C (P5 P95 :-3.0 et 36 %) et la réduction du risque cardiovasculaire. Une analyse de sensibilité par type de traitement suggère qu'une même hausse de HDL-C entre deux classes thérapeutiques pourrait se traduire par un effet clinique dissemblable, indiquant que HDL-C ne peut pas être utilisé comme critère intermédiaire puisqu'il ne serait pas un prédicteur indépendant du risque cardiovasculaire

APA, Harvard, Vancouver, ISO, and other styles

47

Bunce, Michael Anthony. "Chromatin architecture and transcription of the HIV-1 promoter : the role of HMGA." Phd thesis, 2002. http://hdl.handle.net/1885/148641.

Full text

APA, Harvard, Vancouver, ISO, and other styles

48

Vogel, Benjamin. "Organisation von Chromatin durch HMGA1 Proteine." Doctoral thesis, 2011. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-65295.

Full text

Abstract:

HMGA1 Proteine sind kleine, basische, Nicht-Histon Proteine, die in Lösung keine Struktur aufweisen, durch drei AT-Haken, als DNA-Bindungsmotive, gekennzeichnet sind und präferentiell an die kleine Furche der DNA binden. Als differenziell exprimierte Architekturelemente des Chromatins erfüllen sie wichtige Funktionen bei der Regulation DNA abhängiger Prozesse in Zellen und während Entwicklungsprozessen. Aberrante Expressionen führen zu Entwicklungsdefekten und Krebs. In dieser Arbeit wurde der Einfluss von HMGA1 Proteinen auf die Organisation des Chromatins untersucht. Als Modell diente dabei zunächst die Differenzierung von C2C12 Muskelvorläuferzellen. Wie in einer früheren Arbeit gezeigt wurde, ist die Herunterregulation von HMGA1a essentiell für den Eintritt von C2C12 Zellen in die Myogenese. Eine konstante Überexpression von HMGA1a-eGFP hingegen verhindert die Muskeldifferenzierung durch Beeinflussung der Expression myogenesespezifischer Gene und Etablierung einer stabilen Chromatinstruktur. Wie in der vorliegenden Arbeit herausgefunden wurde, nimmt die differenzielle HMGA1a Expression nicht nur Einfluss auf die Expression muskelspezifischer Gene, sondern auch auf die globale Zusammensetzung des Chromatins durch eine reduzierte Expression von H1 Histonen und einer aberranten Expression von HMGB1, HMGN1 und HP1 Proteinen. HMGA1a wurde zusammen mit ORC Proteinen eine Funktion bei der Definition von Replikationsursprüngen in eukaryotischen Zellen zugesprochen. ORC Proteine wurden auch als Komponenten des Heterochromatins und als Interaktionspartner von HP1α identifiziert. Hier konnte mit Hilfe von Co-Immunpräzipitationen, Pull-down Assays und Verdrängungsexperimenten gezeigt werden, dass HMGA1 ein weiterer, direkter Interaktionspartner von ORC Proteinen im Heterochromatin ist und zusammen mit HP1α kooperiert. Pull-down-, Verdrängungs- und siRNA-Experimente zeigten zudem, dass HMGA1 zwar nicht direkt mit HP1α interagiert, die Kooperation der Proteine über ORC aber dennoch wichtig für die Aufrechterhaltung der Heterochromatinsstruktur ist. Damit erweisen sich HMGA1 Proteine als wichtige Stabilisierungsfaktoren des Heterochromatins. Bislang ging man davon aus, dass HMGA1 Moleküle linear, also eindimensional, an ein DNA Molekül binden. Das Vorhandensein von drei DNA-Bindungsmotiven und die eher struktur- als sequenzabhängige Bindung an die DNA lassen vermuten, dass HMGA1 Proteine auch gleichzeitig an benachbarte DNA-Stränge, also auch dreidimensional, binden könnten. Bekräftigt wurde diese Vermutung durch die Bildung von Chromatinaggregaten in Zellen die HMGA1a-eGFP überexprimierten. Dies wurde mittels konfokaler und hochauflösender Mikroskopie (dSTORM) analysiert. Um das Potential einer DNA-Quervernetzung durch HMGA1 Proteine nachzuweisen, wurde eine neue Methode entwickelt. Mit Hilfe eines neuartigen DNA Cross-linking Assays wurde nachgewiesen, dass HMGA1 Proteine in der Lage sind, zwei individuelle DNA Stränge zu vernetzen. Zudem wurde eine neue Domäne in HMGA1 entdeckt die maßgeblich zum Cross-linking beiträgt. Elektronenmikroskopische Analysen bestätigten, dass HMGA1 Proteine in der Lage sind Kreuzungen und Schleifen in DNA Molekülen zu erzeugen. Diese Ergebnisse unterstützen die Vermutung, dass HMGA1 Proteine im Zellkern ein DNA Gerüst bilden können, das Einfluss auf die zelltypische Chromatinorganisation nimmt und dadurch DNA abhängige Prozesse beeinflusst. In wie weit eine HMGA1 induzierte DNA Quervernetzung in vivo zum Beispiel in Chromozentren von C2C12 Zellen oder in Krebszellen, in denen HMGA1 Proteine stark überexprimiert sind, eine Rolle spielen, müssen künftige Untersuchungen zeigen. In dieser Arbeit konnte also gezeigt werden, dass HMGA1 Proteine die Chromatinstruktur auf drei Ebenen organisieren können: Durch Beeinflussung der Chromatinzusammensetzung durch Veränderung der Expression von Chromatinproteinen, durch Interaktion mit anderen Architekturelementen des Chromatins und durch Organisation eines potentiellen DNA Gerüsts
HMGA1 proteins are small basic non-histone proteins characterized by three DNA binding domains, the AT-hooks, which bind to the minor groove of DNA. As differentially expressed architectural chromatin proteins, they perform important functions in the regulation of DNA dependent processes and in development. Aberrant expression leads to developmental defects and cancer. In this thesis the influence of HMGA1 proteins on chromatin organization is investigated. Initially C2C12 myogenic precursor cells were studied, which can be differentiated to myotubes. Previously it had been shown that down-regulation of HMGA1 proteins is crucial for the initiation of myogenic differentiation. Constant over-expression of HMGA1a-eGFP prevents myogenic differentiation by influencing the expression of myogenic genes and by the establishment of a stable chromatin structure. Here it was shown that the differential HMGA1 expression does not only influence the expression of myogenic specific genes but also affects total chromatin composition. This was shown by reduced and aberrant expression of chromatin proteins such as histone H1, HMGB1, HMGN1 and HP1 proteins. Recently it was demonstrated that HMGA1 together with ORC proteins function in origin definition in eukaryotic cells. ORC proteins were also identified as components of heterochromatin and direct interaction partners of HP1α. Here, it was shown by co-immunoprecipitation, pull-down assays, siRNA and displacement experiments that HMGA1 proteins can interact with ORC proteins directly and that they can cooperate with HP1α in heterochromatin. It could be shown that HP1α indeed does not directly interact with HMGA1 but together with ORC proteins is relevant for heterochromatin maintenance. Thus HMGA1 proteins turned out to be important stabilizers of heterochromatin. Until recently it was thought that HMGA1 proteins bind DNA collinearly. In principle the three independent DNA binding AT-hooks of HMGA1 also suggest a concomitant binding to neighboring DNA strands, which could lead to a three dimensional stabilization of DNA. This assumption was affirmed by the occurrence of chromatin aggregates in HMGA1a-eGFP overexpressing cells, which was analyzed by confocal and high resolution (dSTORM) microscopy. By using a newly developed DNA cross-linking assay, which allows the analysis of a DNA crosslinking capability of a protein, it was proven that HMGA1 proteins can bind two individual DNA fibers simultaneously. Furthermore a novel domain in HMGA1 proteins was discovered which is significantly involved in the DNA cross-linking. Electron microscopic analyses confirmed that HMGA1 proteins can specifically generate crossings and loops in DNA molecules. These results support the assumption that HMGA1 proteins can create a DNA scaffold that has influence on cell typical chromatin organization and possibly also affects DNA dependent processes. To what extent HMGA1 induced DNA cross-linking plays a role in vivo, for example in the organization of chromocenters of C2C12 cells or in cancer cells, where HMGA1 proteins are over-expressed, will need to be elucidated in further experiments In summary, this work shows, that HMGA1 proteins influence chromatin structure and composition by affecting the expression of chromatin proteins, by interacting with other architectural chromatin proteins or by producing a higher organization of chromatin on its own

APA, Harvard, Vancouver, ISO, and other styles

49

Schütz, Monika. "Dynamik und Funktion der HMG-Proteine." Doctoral thesis, 2005. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-15627.

Full text

Abstract:

HMG-Proteine sind Architekturelemente des Chromatins und regulieren durch ihre Bindung an das Chromatin auf verschiedene Weise DNA-abhängige Prozesse wie Replikation, Transkription und DNA-Reparatur. Um zu verstehen, wie HMG-Proteine ihre vielfältigen Funktionen erfüllen können, wurde mit Hilfe von EGFP- und DsRed2-Fusionsproteinen ihre Funktion in vivo untersucht. Im Wesentlichen wurde dabei mit Hilfe von Bleichtechniken ihr dynamisches Verhalten charakterisiert. Daneben wurde für die HMGN-Proteine ihr bislang unbekanntes Expressionsverhalten in Tumorzellen bestimmt. So konnte für die HMGN-Proteine gezeigt werden, dass bestimmte Tumorzelllinien (HT-29, FTC-133, MCF-7, RPMI 8226, 697, Ishikawa, LNCap) eine relativ erhöhte Expression von HMGN2 aufweisen, die mit der Tumordifferenzierung korreliert. Eine relativ verringerte Expression von HMGN1 steht dagegen in Mammakarzinomen und Non-Hodgkin-Lymphomen in direktem Zusammenhang mit der Aggressivität der Tumore. Somit kann die HMGN-Expression bei diesen Tumoren als diagnostischer Marker verwendet werden. FRAP-Analysen mit EGFP-Fusionsproteinen führten zu der Erkenntnis, dass HMGN1, HMGN2, HMGA1a, HMGA1b und HMGB1 sich sehr schnell durch den Zellkern bewegen und nur transient an das Chromatin gebunden sind. Es konnte gezeigt werden, dass die spezifischen DNA/Chromatin-Bindungsmotive im Wesentlichen entscheiden, wo die Bindung der HMG-Proteine in vivo erfolgt, ihre Verweildauer im Euchromatin, Heterochromatin und zellzyklusabhängig dann aber durch Modifikationen (Phosphorylierungen, Acetylierungen) reguliert wird. Dies wurde beispielhaft durch punktmutierte und deletierte Fusionsproteine, sowie durch Inkubation der Zellen mit spezifischen Drogen für die HMGA1a-Proteine gezeigt. FRAP-Analysen haben außerdem gezeigt, dass die Spleißvarianten hHMGA1a und hHMGA1b unterschiedliche kinetische Parameter besitzen. Dies zeigt, dass beiden Varianten unterschiedliche Funktionen zugesprochen werden können. Die gefundenen spezifischen, transienten Verweildauern der einzelnen HMG-Proteine führen zu einem Modell eines dynamischen Chromatin-Netzwerkes, wobei alle HMG-Proteine in Wechselwirkungen innerhalb eines dynamischen Chromatinprotein-Cocktails DNA-abhängige Prozesse regulieren können. Die jeweiligen, wie hier gezeigt, durch Modifikationen regulierten Verweildauern der HMG-Proteine bestimmen darüber, welche anderen Chromatinproteine wie lange am Chromatin verbleiben und bestimmte Funktionen, wie beispielsweise die Modifikation der Core-Histone, übernehmen können. Die dynamischen Parameter einzelner HMG-Proteine erklären so, wie diese Proteine ihre vielfältigen Funktionen als Architekturelemente und bei der Regulation DNA-abhängiger Prozesse erfüllen können. Einige Vertreter, wie die HMGB1-Proteine, bewegen sich so schnell durch den Zellkern, dass ihre kinetischen Parameter durch das beschränkte zeitliche Auflösungsvermögen konfokaler Mikroskope der älteren Generation nicht erfassbar sind. Die Bestimmung von Dosis-Wirkungs-Beziehungen von Drogen, welche die kinetischen Parameter von HMGB1-Proteinen beeinflussen können, ist inzwischen mit Mikroskopen der neuen Generation möglich. Im Verlaufe der Arbeit zeigte sich, dass andere verwendete Fluorophore wie DsRed2 die kinetischen Eigenschaften von HMG-Fusionsproteinen beeinflussen können. Durch eine erhöhte Verweildauer können auch sehr transiente Interaktionen sichtbar gemacht werden. Wie gezeigt wurde, kann eine erhöhte Verweildauer aber auch zur Verdrängung anderer Proteine führen, die die gleichen Bindungsstellen benutzen und so eine Modulation des Chromatins bewirken. Die Nutzung von DsRed-Fluorophoren ermöglicht interessante neue Erkenntnisse. Diese müssen aber stets vor dem Hintergrund eines veränderten dynamischen Verhaltens der Fusionsproteine interpretiert werden. Zusammengenommen liefern die hier vorgestellten Ergebnisse zur Dynamik der HMG-Proteine grundlegende Informationen, die zur Klärung ihrer Funktion bei Chromatinmodulationen, etwa bei Differenzierungsprozessen oder der Entstehung von Tumorzellen entscheidend beitragen. Die Erkenntnis, dass diese Proteine lediglich transiente Interaktionen mit ihren Bindungspartnern eingehen können, sind im Hinblick auf die Behandlung von Tumoren, bei denen HMG-Proteine im Vergleich zu Normalgewebe häufig überexprimiert sind, von großer Bedeutung
HMG proteins are architectural chromatin proteins that regulate different DNA dependent processes such as replication, transcription and DNA repair. To understand how HMG proteins manage to fulfill their multiple functions they were investigated in vivo with the help of EGFP and DsRed2 fusion proteins. Using photobleaching techniques their dynamic properties were characterized in detail. Furthermore, the expression pattern of HMGN proteins in tumor cell lines was investigated for the first time. As presented in this thesis, it was found that HMGN2 proteins exhibited an elevated expression level in some tumor cells (HT-29, FTC-133, MCF-7, RPMI 8226, 697, Ishikawa, LNCap) correlating with the tumor differentiation status. In contrast a reduced expression of HMGN1 found in Mammacarcinoma and Non-Hodgkin-Lymphoma correlated with tumor aggressiveness. Therefore the analyses of HMGN expression may be a suitable diagnostic marker at least in the tumors investigated. FRAP analyses with cells expressing EGFP fusion proteins revealed that HMGN1, HMGN2, HMGA1a, HMGA1b and HMGB1 move very rapidly through the cell nucleus and only bind transiently to chromatin. It was demonstrated that the decision where HMG proteins bind in vivo is essentially mediated by their specific DNA binding motifs. However, the individual residence times in eu- or heterochromatin and chromosomes are regulated by protein modifications (phosphorylation, acetylation). This has been demonstrated using point mutated and truncated HMGA fusion proteins and by the application of specific drugs as well. FRAP analyses also indicated that the splice variants HMGA1a and HMGA1b exhibit different kinetic properties. This supports the view that both variants have different functions. The kinetic parameters characteristic for each HMG protein lead to a model of a dynamic chromatin network in which all HMG proteins are able to regulate DNA dependent processes via multiple interactions with other proteins as components of a cocktail of dynamic chromatin proteins. In this model, individual residence times of all HMG proteins which are regulated by secondary modifications would determine how long other chromatin modulating proteins could reside on chromatin. Therefore the dynamic parameters of the HMG proteins directly affect the capability of other proteins to modulate chromatin structure, e.g. by modifications of core histones. This explains the multiple functions of HMG proteins in chromatin packaging and function. The kinetic parameters of some rapidly moving members of the HMG protein family, such as HMGB1, are beyond the time resolution capacities of most confocal microscopes. However, novel setups of modern confocal microscopes are now capable to determine the dynamic parameters of HMGB proteins and allow investigations of drug induced effects on HMGB dynamics. Control experiments revealed that other fluorophors such as DsRed2 modulate the dynamic parameters of HMG fusion proteins. Due to an increased residence time of HMG DsRed2 fusion proteins it is possible to monitor even very transient interactions. Moreover, it could be observed that this increased residence time may interfere with binding of other proteins (i.e. proteins which occupy the same binding sites) leading to a reorganization of chromatin. Thus, fusion proteins with DsRed fluorophores may be used as helpful tools to investigate protein functions. However, results should always be considered against the background of DsRed modulated kinetics and thus they should be interpreted very carefully. Taken together the results presented in this thesis provide novel information about the dynamic behaviour of HMG proteins which is crucial to understand how chromatin is modulated during differentiation processes or development of neoplasia. Their transient interactions with DNA or other proteins and the fact that overexpression correlates with tumor progression might be relevant for the development of novel strategies for tumor treatment

APA, Harvard, Vancouver, ISO, and other styles

50

An, Woojin. "Interaction of linker proteins, H1 and HMG1, with nucleosome reconstituted on positioning sequences." Thesis, 1998. http://hdl.handle.net/1957/33954.

Full text

APA, Harvard, Vancouver, ISO, and other styles

Dissertations / Theses on the topic 'HMGA proteins'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles