Global ETD Search

41	Mécanismes transcriptionnels gouvernés par Fra-1 et Fra-2 dans les cancers du sein agressifs / Transcriptionnal mechanisms governed by Fra1 and Fra-2 in agressive breast cancer. Moquet-Torcy, Gabriel 13 December 2011 (has links) Le cancer du sein est la principale cause de mortalité par cancer chez la femme. Deux des facteurs de transcription de la famille Fos, Fra-1 et Fra-2, sont surexprimés dans les cancers du sein agressifs et contribuent au phénotype tumoral en favorisant entre autres, la prolifération, la motilité et l'invasivité. De façon surprenante, les mécanismes moléculaires via lesquels Fra-1 et Fra-2 (et plus généralement le complexe transcriptionnel AP-1 dont ils sont des constituants) gouvernent la transcription de leurs gènes cibles sont quasi-inconnus. Dans ce contexte, en combinant diverses approches (immunoprécipitation de chromatine, interférence à l'ARN…), j'ai étudié les mécanismes moléculaires par lesquels Fra-1 et Fra-2 contrôlent la transcription dérégulée du gène de l'urokinase ou uPA (sérine protéase cruciale dans la progression tumorale et l'établissement de métastases) qui est l'un des nouveaux marqueurs utilisés en clinique pour la mise en place des choix thérapeutiques. Mes travaux montrent de façon originale que (i) Fra-1 et Fra-2 agissent de façon non redondante et coopèrent pour réguler l'expression d'uPA via leur fixation sur un enhancer AP-1 localisé à -1,9 kb du site d'initiation de la transcription (TSS), (ii) Fra-2 est nécessaire au recrutement de RNA Pol II au niveau de l'enhancer, tandis que Fra-1 stimule le passage de RNA Pol II de sa forme initiatrice à sa forme élongatrice et (iii) que la polymérase recrutée à l'enhancer rejoint le TSS par un mécanisme de « tracking », très rarement décrit dans la littérature, en produisant de petits ARNs non codants, bidirectionnels et instables. / Breast cancer is the most frequent malignant disease among women. Two transcription factors, Fra-1 and Fra-2, belonging to the Fos family members, are overexpressed in aggressive breast cancers and contribute to the tumorigenic phenotype by favoring proliferation, motility and invasion. Surprisingly, the molecular mechanisms governed by Fra-1 and Fra-2 (and more generally by the AP-1 transcriptional complex, which they are components of) for the transcription of their target genes are still largely unknown. In this context, by combining different approaches (chromatin immunoprecipitation, RNA interference…), I studied the molecular mechanisms orchestrated by Fra-1 and Fra-2 for the expression of the urokinase (or uPA) gene (encoding a serine protease crucial for tumor progression and metastasis), which is one of the new diagnostic markers now taken into consideration for deciding therapeutic strategies. Interestingly, my results show that (i) Fra-1 and Fra-2 have non redundant functions and cooperate for the transcriptional regulation of uPA through their binding to AP-1 enhancer located 1.9 kb upstream of the transcriptional start site (TSS), (ii) Fra-2 is required for the recruitment of RNA Pol II on this enhancer while Fra-1 allows the conversion of RNA Pol II initiating form into its elongating form and (iii) enhancer-recruited RNA Pol II reaches the TSS by a tracking mechanism, mechanism very rarely described in the literature, during which it synthetizes small, unstable bidirectional, non coding RNAs. Fra-1; Fra-2; AP-1 Enhancer Régulation de la transcription UPA (urokinase) Activateur du plasminogène RNA Pol II-Trackingcancer du sein Fra-1; Fra-2; AP-1 Enhancer Transcription regulation Urokinase plasminogen activator RNA Pol II-Tracking Breast cancer
42	Receptor mediated catabolism of plasminogen activators Grimsley, Philip George, Medical Sciences, Faculty of Medicine, UNSW January 2009 (has links) Humans have two plasminogen activators (PAs), tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), which generate plasmin to breakdown fibrin and other barriers to cell migration. Both PAs are used as pharmaceuticals but their efficacies are limited by their rapid clearance from the circulation, predominantly by parenchymal cells of the liver. At the commencement of the work presented here, the hepatic receptors responsible for mediating the catabolism of the PAs were little understood. tPA degradation by hepatic cell lines was known to depend on the formation of binary complexes with the major PA inhibitor, plasminogen activator inhibitor type-1 (PAI-1). Initial studies presented here established that uPA was catabolised in a fashion similar to tPA by the hepatoma cell line, HepG2. Other laboratories around this time found that the major receptor mediating the binding and endocytosis of the PAs is Low Density Lipoprotein Receptor-related Protein (LRP1). LRP1 is a giant 600 kDa protein that binds a range of structurally and functionally diverse ligands including, activated α2 macroglobulin, apolipoproteins, β amyloid precursor protein, and a number of serpin-enzymes complexes, including PA??PAI-1 complexes. Further studies for the work presented here centred on this receptor. By using radiolabelled binding assays, ligand blots, and Western blots on cultured cells, the major findings are that: (1) basal LRP1 expression on HepG2 is low compared to a clone termed, HepG2a16, but appears to increase in long term culture; (2) a soluble form of LRP1, which retains ligand-binding capacity, is present in human circulation; (3) soluble LRP1 is also present in cerebral spinal fluid where its role in neurological disorders such as Alzheimer??s disease is a developing area of interest; and (4) the release of LRP1 is a mechanism conserved in evolution, possibly as distantly as molluscs. The discovery, identification, and characterisation of soluble LRP1 introduces this protein in the human circulation, and presents a possible further level of regulation for its associated receptor system. LRP1 Soluble receptor Soluble LRP1 Radioisotopes Western blotting Tissue-type plasminogen activator Monoclonal antibodies Recombinant protein production SDS-PAGE electrophoresis Flow cytometry Ligand blotting tPA Urokinase-type plasminogen activator Alzheimer's disease uPA Clearance Endocytosis Degradation Evolutionary conservation HepG2 hepatoma cell line Plasminogen activator inhibitor type-1 PAI-1 Serpin enzyme complexes Fibrinolysis Atherosclerosis Vascular biology
43	Reordering of Meaningful Worlds : Memory of the Organization of Ukrainian Nationalists and the Ukrainian Insurgent Army in Post-Soviet Ukraine Yurchuk, Yuliya January 2014 (has links) After the collapse of the Soviet Union, Ukrainian society faced a new reality. The new reality involved consolidation and transformation of collective identities. The reinvigoration of national identity led to a change in the emphasis on how the past was dealt with – many things which were regarded as negative by the Soviet regime became presented as positive in independent Ukraine. The war-time nationalist movement, represented by the Organization of Ukrainian Nationalists (OUN) and the Ukrainian Insurgent Army (UPA), became one of the re-configured themes of history. While most of the studies of memory of the OUN and UPA concentrated on the use of the history of the OUN and UPA by nationalist parties, this study goes beyond the analysis of such use of history and scrutinizes the meaning of this history in nation- and state-building processes in relation to memory work realized on the small-scale regional and local levels with the main focus on Rivne and Rivne oblast’. Moreover, this book focusses not only on the “producers” of memory, but also on the “consumers” of memory, the area which is largely understudied in the field of memory studies. In the book the main emphasis is put on monuments which are regarded as catalysts and symptoms of memory. The present study showed that the OUN and UPA are used more as the metaphors of the anti-Soviet and anti-communist struggle for independence than as historical entities. This past is largely mythologized. Functioning as a myth the memory of the OUN and UPA obliterates difficult knowledge that the historical research reveals on the questionable activities and ideology of those organizations. As a result, the past of the OUN and UPA is re-imagined, re-filled with new meanings so that it is used along even with the democratic and pro-European claims in the present. It was especially well-observed during the Orange Revolution in 2004 and during the Euromaidan in 2013-2014, when the European Union’s flags were seen next to the OUN’s red-and-black flags or when the pro-European slogans were proclaimed alongside the OUN and UPA slogans. At the same time, the results demonstrated an intricate complexity of memory work shaped by intensive dynamics of private and public, grassroots and official, local and national encounters. Although there have been attempts made by political actors to draw a direct link between the national identity, political allegiances and proposed heroic version of memory, the study showed, that such attempts did not really work. In the pluralistic context the meanings are too fluid and adherence to one version of history does not preclude adherences to other versions of history which are presented as diametrically opposite in the political sphere. As result, on the recipients’ grassroots level, the memory reveals its amalgamated characteristics. Drawing on studies about post-colonial subjectivities and theories of remediation developed in memory studies, this book explores the changes in memory culture of contemporary Ukraine and examines the role of memory in producing new meanings under the rapidly changing conditions after the collapse of the Soviet Union up to 2014. The book contributes to the studies of memory culture in post-Communist countries as well as to the studies of society in contemporary Ukraine. Ukraine memory Organization of Ukrainian Nationalists OUN Ukrainian Insurgent Army UPA Rivne monuments Volhynia historical representations reception of history nationalism nation-building state-building commemoration narrative analysis Klym Savur Taras Bul'ba-Borovet's Hurby Euromaidan Orange Revolution post-Soviet post-colonial reclamation history-writing difficult knowledge remediation premediation myth Second World War ОУН УПА пам'ять комеморація пам'ятник Рівне Волинь рецепція історії міф Друга світова війна minne minneskulturen myt Ukrainska upprorsarmén reception av monument monument problematisk kunskap

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