The human androgen receptor (hAR) is a member of the steroid receptor family of nuclear receptors (NRs) that acts as a ligand-activated transcription factor. Mutations in the androgen receptor impair normal male sexual development resulting in a clinical continuum of virilization disorders known as the androgen insensitivity syndrome (AIS). Characterization of key AR mutations has enabled a better understanding of structure-function relationships of the AR, and serves as a prototype for steroid receptor mechanisms of action. / NH2-/COOH-terminal (N/C-terminal) interactions appear to be critical for AR function in vivo as evidenced by the association of AIS with single amino acid mutations that disrupt the N/C-interaction. / In the first paper, we examine the effects of five distinct C-terminal mutations on hAR N/C-interactions in the presence and absence of the hAR coactivator, TIF2. We found that each of the mutations disrupted normal hAR N/C-interactions, partially explaining the molecular defects underlying the corresponding AIS phenotypes. Interestingly, we show a strong correlation between the strength of N/C-interaction and the phenotypic degree of AIS observed. / In the second paper, we investigated the role of N-terminal mutations on hAR N/C-interactions, in the presence and absence of TIF2. While there have been no previous reports of the effects of N-terminal hAR mutations on N/C-interaction, we show that two distinct mutations in this terminal of the hAR are directly responsible for the disruption of normal N/C-interaction in a patient with complete androgen insensitivity. We suggest that these mutations affect the N/C-coactivator-binding interface, thus reducing the overall transcriptional competence of the hAR.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.80273 |
| Date | January 2002 |
| Creators | Ghali, Shereen |
| Contributors | Trifiro, Mark A. (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 | Master of Science (Department of Human Genetics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002059223, proquestno: AAIMQ98642, Theses scanned by UMI/ProQuest. |
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