Met is a transmembrane receptor tyrosine kinase whose ligand is hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF stimulates epithelial cell mitogenesis, motility and branching tubulogenesis. Met and HGF/SF are essential for embryonic development, and are implicated in oncogenesis. In this thesis, the possible role of Met in the development of human breast cancer is examined. The MET gene is located at chromosome 7q31, a region frequently deleted in breast cancer. In this thesis, I demonstrate that MET is included in the smallest common region of deletion of chromosome 7q31 in breast cancer, and is therefore a candidate for a breast cancer tumor suppressor gene. To investigate this further, I elucidated the intron-exon structure of the MET gene. The MET gene is composed of 21 exons, spanning approximately 130 kilobases(kb) of chromosomal DNA. Interestingly, the first coding exon of MET, exon 2, is unusually large, at 1214 nucleotides (nt). Exon 2 is subject to alternative splicing in all epithelial cells studied, and is skipped to produce a 7kb mRNA species which does not encode a protein product. Furthermore, in seven of 13 human breast cancer cell lines studied, exon-skipping of MET exon 2 occurs more frequently when compared to two immortalized breast epithelial cell lines. These seven breast cancer cell lines have an altered ratio of Met mRNA isoforms, with increased levels of the non-protein-encoding 7kb exon 2-skipped mRNA, and a corresponding decrease in the expression of Met receptor in these cells. Significantly, in all other carcinoma types studied to date, the Met receptor is expressed at high levels, as in normal epithelial cells, indicating that loss of Met protein is specific to breast carcinoma cells. The alteration in the normal splicing pattern of MET is correlated with alterations in the normal pattern of expression of SR splicing proteins, which are responsible for regulating alternative splicing. I propose that loss of Met is an event s
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.37764 |
| Date | January 2001 |
| Creators | Lin, Jenny Catherine, 1970- |
| Contributors | Park, Morag (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001802028, proquestno: NQ70080, Theses scanned by UMI/ProQuest. |
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