A hallmark of DNA methylation is the fact that 60 to 80% of CpG dinucleotide sequences in the vertebrate genome are methylated at the 5th-position of cytosine while the remaining unmethylated sequences are nonrandomly distributed throughout the genome generating a pattern of methylation that is both tissue and gene specific. Several lines of evidence suggest that methylation patterns correlate with the expression level of eukaryotic genes and that DNA methylation plays an important role in regulating the state of differentiation of mammalian cells. The methylation of DNA is catalyzed by the DNA methyltransferase (DNA MeTase) enzyme, which transfers a methyl group from S-adenosylmethionine to DNA. Cells that exhibit different DNA methylation patterns express similar mRNA levels and DNA MeTase activities. It has therefore been suggested that patterns of methylations are the result of an interplay between the level of the nonspecific DNA MeTase enzyme and other site- or tissue-specific nuclear factors; changing either one of these parameters will result in a change in DNA methylation patterns. In accordance with this hypothesis it has been proposed that regulation of DNA methyltransferase gene expression plays a role in the maintenance and generation of DNA methylation patterns, as is the case in prokaryotic systems. Bestor et al., cloned the cDNA encoding the mouse DNA MeTase gene but nothing was known about the elements regulating its expression. To further understand regulation of the mouse DNA MeTase gene expression I cloned and sequenced the 5$ sp prime$-upstream region of the gene and demonstrated that: (A) The mouse DNA MeTase promoter is a unique housekeeping promoter lacking the classical binding sites for known transcription factors. (B) The mouse DNA MeTase is induced by the Ras-AP-1 pathway. (C) Induction of the mouse DNA MeTase by the Ras-AP-1 leads to profound changes in cell morphology, methylation patterns and tumorigenicity all of which can be inhib
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.29122 |
| Date | January 1995 |
| Creators | Rouleau, Julie |
| Contributors | Szyf, Moshe (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 (Department of Pharmacology & Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001468335, proquestno: NN08152, Theses scanned by UMI/ProQuest. |
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