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Cooperative binding mechanisms leading to the specific androgen receptor regulation of target genes

University of British Columbia

Genes uniquely regulated by the androgen receptor (AR) typically contain multiple androgen response elements (AREs) that in isolation are of low DNA binding affinity and transcriptional activity. However, specific combinations of AREs in their native promoter context results in highly cooperative DNA binding by AR and high levels of transcriptional activation. Within this study, we demonstrate that the natural androgen-regulated promoters of PSA and Probasin contain two classes of AREs dictated by their primary nucleotide sequence that function to mediate cooperativity. Class I AR-binding sites display conventional guanine contacts. Class II AR-binding sites have distinctive atypical sequence features and upon binding to AR the DNA structure is dramatically altered through allosteric interactions with the receptor. Class II sites stabilize AR-binding to adjacent Class I sites and result in synergistic transcriptional activity and increased hormone sensitivity. The specific nucleotide variation within the androgen receptor binding sites dictate was determined to dictate differential functions to the receptor. The potential role of individual nucleotides within Class II sites and predicted consensus sequences for Class I and II sites was also identified. Our data suggest that this may be a universal mechanism by which AR achieved unique regulation of target genes through complex allosteric interactions dictated by primary binding sequences.

Thesis/Dissertation

application/pdf

2009-08-06

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http://hdl.handle.net/2429/11966

Pathology

University of British Columbia

UBCV

DSpace