To elucidate mechanisms involved in the regulation of a number of mammalian cell differentiation events, studies were performed to characterize the transcriptional repression functions of the Groucho/TLEs, Hairy and Enhancer of split (Hes), and Runt-related (RUNX) protein families. These proteins have been shown to have overlapping or antagonistic roles in a number of cell differentiation processes, in both Drosophila and mammals. More specifically, the aim was to elucidate mechanisms by which Hes and RUNX-mediated transcriptional control is modulated, with respect to their interactions with each other and the Groucho/TLE proteins. / It is shown here that mammalian Hes1 requires TLEs to repress gene expression, similar to the requirement Drosophila Hes proteins have for Groucho. It is shown further that TLEs also interact with mammalian RUNX proteins and inhibit RUNX's ability to transactivate gene expression. In contrast, Hes1 also physically associates with RUNX and enhances RUNX-mediated transactivation. These results, together with our additional finding that RUNX can inhibit Hes1-mediated transcriptional repression, suggest for the first time that RUNX and Hes1 proteins regulate each other's transcriptional functions. / This thesis also shows that Hes1 can be found in a discreet nuclear subcompartment involved in the regulation of gene expression, termed the nuclear matrix. Nuclear matrix binding is mediated by the same Hes1 C-terminal domain that acts as a binding site for Groucho/TLEs, which also localize to the nuclear matrix and are required for Hes1-mediated transcriptional repression. Both the nuclear matrix association and transcription repression activity of Hes1 are inhibited by deletion of its C-terminal region, indicating that Groucho/TLEs act as transcriptional corepressors for Hes1. / Together, the material presented in this thesis suggests that Hes1 and RUNX proteins interact with each other to modulate gene expression in the development of a number of tissues.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.38233 |
| Date | January 2001 |
| Creators | McLarren, Keith W. |
| Contributors | Stifani, Stefano (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 Neuroscience.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001861854, proquestno: NQ78730, Theses scanned by UMI/ProQuest. |
Page generated in 0.0017 seconds