HOX proteins are evolutionarily conserved homeodomain (HD)-containing transcription factors that mediate environmental signal cues and specify regional identities. PBC (including EXD in Drosophila and PBX in vertebrates) and MEIS/PREP proteins are two families of transcription factors within the broader three-amino-acid-loop-extension (TALE) class of homeoproteins. They form cooperative DNA-binding complexes with HOX proteins and have been shown to assist HOX functional specificity and participate in HOX-mediated transcriptional regulation. / The function of HOX cofactors is regulated at multiple levels. The availability of PBC proteins is controlled via differential subcellular localization which is partially directed by MEIS. However, cytoplasmic anchoring factors could also contribute to PBX subcellular localization. Part of this thesis project is devoted to identifying such factors. A cytoplasmic retention factor, non-muscle myosin II heavy chain B (NMHCB) has been uncovered as a PBX-interacting protein via a yeast two-hybrid screen. The NMHCB fragment induces cytoplasmic retention of PBX and EXD in both mammalian cells and Drosophila S2 cells. In addition, the subcellular distribution of EXD is deregulated in Drosophila bearing a mutated zipper gene, a homolog of mammalian NMHCB. These results reveal a conserved mechanism that promotes the cytoplasmic localization of PBX and EXD. / Nuclear PBX and MEIS form cooperative complexes with subsets of HOX proteins. In this project, we further study the transcriptional activity of MEIS-PBX-HOX heterotrimers and try to dissect the role of the third partner in the complex. We show that MEIS1 is recruited to the Hoxb1 auto-regulatory element (ARE), a known PBX-HOX target, in conjugation with RA-induced Hoxb1 transcriptional activation in P19 cells. We map TSA- and protein kinase A (PKA)-responsive transactivation domains to the C-termini of MEIS1 proteins. We propose that cell signaling modulates the transcriptional activity of MEIS and MEIS-PBX-HOX complexes through this region. In addition, the DNA binding of MEIS and protein-protein interaction between MEIS and PBX both contribute to the activity. Moreover, the C-terminal regions appear to confer functional differences among MEIS/PREP family proteins.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84260 |
| Date | January 2003 |
| Creators | Huang, He, 1972- |
| Contributors | Featherstone, Mark (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: 002032080, proquestno: AAINQ98275, Theses scanned by UMI/ProQuest. |
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