Global ETD Search

1	Regulation of cell cycle and differentiation by ASCL1 in Glioblastoma McNally, Aoibheann January 2018 (has links) Glioblastoma multiforme (GBM) is the most aggressive primary brain tumour in adults, as well as the most common. The current standard therapy is maximal safe resection, followed by radiotherapy in combination with the alkylating agent, temozolomide. Despite this multi-model treatment approach, median survival is just 14.6 months and new therapies are urgently needed. Glioblastoma stem cells (GSCs) are a highly tumourigenic subpopulation of GBM cells believed to promote therapeutic resistance along with angiogenesis and metastasis. Cancer stem cells share crucial characteristics with normal stem cells such as their ability to self- renew, maintain proliferation and differentiate multi-potently. One strategy to target GSCs is to force them to differentiate into post-mitotic cells, as this would cause them to lose their long-term repopulation potential and would therefore limit tumour growth. In this study, I investigated if the transcription factor ASCL1 could drive neuronal differentiation in GSCs. ASCL1 is a key regulator of neurogenesis in the developing CNS and is sufficient to reprogramme fibroblasts, astrocytes and induced pluripotent cells into neurons. However, ASCL1 also promotes proliferation, and in GSCs, it has been shown to drive tumourigenesis by upregulating Wnt signaling. Given its role in two opposing functions, ASCL1 is tightly regulated by multi-site phosphorylation on serine-proline resides. It is phosphorylated when driving proliferation in cycling cells and is un(der)phosphorylated when activating the transcription of its downstream targets involved in differentiation. I found that endogenous ASCL1 was phosphorylated in GSC lines and hypothesized that dephosphorylating ASCL1 may drive differentiation. I tested this by overexpressing a phosphomutant form of ASCL1, and found that it drove cell cycle exit through the downregulation of Cyclin D2, CDK4 and CDK6. However, ASCL1 did not drive overt differentiation which suggests GSCs may not respond to differentiation cues.
2	Mi-2 chromatin remodeling factor functions in sensory organ development through proneural gene repression in Drosophila YAMASAKI, Yasutoyo, NISHIDA, Yasuyoshi January 2006 (has links) No description available. NuRD complex chromatin remodeling factor sensory organ development proneural gene macrochaete
3	Investigations of Proneural Glioblastoma to Identify Novel Therapeutic Targets Boije, Maria January 2011 (has links) Malignant glioma is a highly lethal and destructive disease with no proper cure. We have investigated some of the hallmarks of cancer in connection to glioma and found ways to disrupt these and prevent tumor growth. The work is done within the context of a glioma subtype distinguished by activation of PDGF signaling termed the proneural subtype. In two of the studies we have investigated mechanisms regulating the glioma cells themselves, and in the other two we have focused on the tumor stroma. In the first study, glioma-initiating cells were isolated in defined serum free culture medium from PDGF-B driven murine glioma and shown to be independent of EGF and FGF2 for self-renewal and proliferation. When cultured in serum the GICs displayed an aberrant differentiation pattern that was reversible. Specific depletion of the transduced PDGF-B caused a loss of self-renewal and tumorigenicity and induced oligodendrocyte differentiation. The transcription factor S-SOX5 has previously been shown to have a tumor suppressive effect on PDGF-B induced murine glioma, and to induce cellular senescence in PDGF-B stimulated cells in vitro. We found that S-SOX5 had a negative effect on proliferation of newly established human glioma cells cultured under stem cell conditions. We also revealed a connection between alterations causing up-regulation of SOX5 with the proneural subgroup and a tendency towards co-occurrence with PDGFRA alterations. Angiogenesis, the formation of new blood vessels from existing ones, is an important hallmark for glioma malignancy. We found that the anti-angiogenic protein HRG had a negative effect on glioma progression in PDGF-B induced experimental tumors and that HRG was able to completely prevent formation of glioblastomas. Subsequently it was shown that HRG could skew pro-tumorigenic tumor associated macrophages into an anti-tumorigenic phenotype. Stromal cells had not previously been fully investigated in gliomas. We observed a correlation between tumor malignancy and increased numbers of tumor-associated macrophages as well as pericytes in PDGF-B induced gliomas. There was also a correlation between tumor grade and vessel functionality that had not previously been shown. Our results offer further understanding of gliomagenesis and present possible future therapies. Glioma proneural subtype hallmarks glioma initiating cells S-SOX5 angiogenesis stromal cells Tumour biology Tumörbiologi
4	The early development of the inner ear: the role of notch and fgf pathways in aerly otic neural versus non-neural patterning Abelló Sumpsi, Gina 25 January 2008 (has links) Otic neuronal precursors are specified in the otic placode but interestingly do so only in the anterior domain of the otic placode, the proneural domain. In the present study, we have explored why only this territory has the competence to undergo neurogenesis, this means the early events of otic proneural regionalization and neural commitment. The proneural and non-neural domains presented complementary gene expression patterns of transcription factors and members of the Notch pathway. Overall, we propose that proneural character is acquired in the anterior territory by the action of localized ectodermal FGF8-FGF10 signaling that enhances Sox3 function. FGF signals through Sox3 activity would be essential for the specification of the proneural domain versus a non-neural territory, while Notch would be involved in refining this early regionalization. / Els precursors neurals de la oïda són especificats dins un subdomini de la placoda acústica, el domini proneural. En aquesta tesis doctoral, s'ha explorat la raó per la qual la competència neural només és adquirida en aquest subdomini. Els dominis neural i no-neural del territori presenten dominis d'expressió genètica complementaris. Aquest treball proposa que el caràcter proneural és adquirit en el subdomini anterior del territori per l'acció de FGF8 i FGF10 localitzats en lï¿½ectoderm ï¿½tic que promouen lï¿½acciï¿½ de Sox3. De manera que, les senyals FGF i lï¿½activitat Sox3 sï¿½n essencials per lï¿½especificaciï¿½ del domini proneural, mentre que la via Notch ï¿½s necessï¿½ria per refinar la regionalitzaciï¿½ final entre un domini neural complementari a un domini no-neural. ratolí peix pollet embrió cultius d'embrió electroporació marcatge cellular Sox3 resctricció de llinatges Notch FGF territori no-neural neurona territori proneural regionalització oída Desenvolupament lineage restrictions embryo culturing cell labelling electroporation DiI mouse zebrafish chick embryo otic placode neurogenesis DAPT Sox3 patterning signaling FGF proneural Notch Development 57 61

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