A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg in fulfilment of the requirements for the degree of Master of Science (Haematology) / The region Ilpl3-pl5 on the short arm of chromosome 11 (lip) has been implicated in the initiation or progression of several human malignancies including the embryonic rhabdomyosarcoma Wilms' tumour, bladder, renal cell and ovarian carcinoma. In this study, Fluorescence In Situ hybridisation (FISH) was used to identify the nature of a chromosome llp+ abnormality present in two ovarian carcinoma cell lines after conventional cytogenetic techniques had failed to elucidate the chromosomal origin of the abnormality. Using whole chromosome library probes, the abnormality in cell line UW0V2 was found to be composed entirely of chromosome 3 material representing the translocation t (3;11) (pl2-14;pl5). In the protein-free subline UW0V2(Sf), the abnormality was found to consist of the complex translocation t (3;8; 11) (pl2-14 ;q22-24;pl5) . It is possible that the involvement of chromosome 8 in this translocation was a cell culture phenomenon. Other structural and numerical abnormalities elucidated with FISH in cell line UW0V2(Sf) included lq+, +5, +7, 7q-, 8q+, +12, +14, 14q+, -15, 16q- and -18. Using FISH together with the gene probe pSB|5 and the CEPH YAC probes 892g9, 785e5, 847al2, 954f4, 966e8 and 845a3, the breakpoint region on chromosome 11 in the _ two cell lines was narrowed down and mapped to the region Ilpl4.3-pl5.1 lying between probes 966e8 (D11S902) and 845a3 (D11S899). This represents a physical distance of approximately 1 Mb. The breakpoint in the two cell lines appeared to involve the same region on llplS.l. In a separate study, three epithelial ovarian tumour specimens and four ascitic fluid specimens were obtained. Tumour specimens T2 and T4 and ascitic fluid specimens AF-1, AF-2 and AF-3 were all cytogenetically uninformative. Cytogenetic analysis of specimen T5 revealed a single clonal abnormality involving a deletion in the region 6q21. Ascitic fluid specimen AF-5 yielded cytogenetically normal metaphases. Both specimens were hypodiploid and revealed a cytogenetically normal chromosome 11. Using FISH and CEPH YAC probes 966e8 and 845a3, no abnormalities were detected in the region llpl4.3-pl5.1 in these two specimens but one cannot rule out the possibility of submicroscopic abnormalities lying within the region between these probes. From this study we speculate that chromosome 6 abnormalities may be important in the initiation of these tumours. From the results obtained with cell lines UW0V2 and UW0V2 (Sf) we speculate that the chromosome 3 abnormalities were an early event in the evolution of these tumours while the chromosome 11 abnormality was a later event. Little is known about the region llpl4.3-pl5.1 and very few disease loci have been assigned to this region, however, we may speculate that this region harbours a tumour suppressor gene or an oncogene whose disruption or activation is critical to the pathophysiology of ovarian carcinoma and other genitourinary cancers. / WHSLYP2017

L1-type cell adhesion molecule (L1CAM) plays an essential role in the development of nervous system and is also highly relevant for the progression of diseases such as Alzheimer’s disease, stroke and cancers, some of the leading causes of human mortality. In addition to its canonical role as a plasma membrane protein organizing the cytoskeleton, recent in vitro studies have revealed that transmembrane as well as cytosolic fragments of proteolytically cleaved vertebrate L1CAM translocate to the nucleus and regulate expression of genes involved in DNA post-replication repair, cell cycle control, migration and differentiation. However, little is known about the in vivo function of L1CAM in the adult nervous system. This dissertation research focuses on studying in vivo nuclear translocation and function of L1CAM. Using the Drosophila model system, we first show that the sole Drosophila L1CAM homolog, Neuroglian (Nrg), is proteolytically cleaved by Alzheimer’s associated secretases, similar to L1CAM, and is also translocated to the nucleus in the adult nervous system. Subsequently, we have shown that the deletion of highly conserved Ankyrin binding domain or FIGQY motif disrupts nuclear import. Further experiments have revealed that the nuclear translocation of Nrg is in fact regulated by the phosphorylation of the FIGQY motif. Importantly, our studies also show transgenic expression of full-length Nrg or the intracellular domain of Nrg resulted in increased myc expression, which is associated with increased sensitivity to oxidative stress and reduced life span. On the other hand, deletion of the FIGQY motif or mutations preventing its phosphorylation led to decrease in myc expression. In summary, we have identified a novel role for the highly conserved Ankyrin binding domain in nuclear translocation and transcriptional regulation of the Drosophila myc oncogene, which is of high relevance to neurodegenerative diseases and cancer associated with oxidative stress. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.