The standard treatment for advanced prostate cancer is chemical castration, which inhibits the activity of the androgen receptor (AR). Eventually, prostate cancer reemerges with a castration-resistant phenotype (CRPC) but still depends on AR signaling. One mechanism of AR activity in CRPC is the synthesis of AR splice variants, which lack the ligand binding domain. These splice variants function as constitutively active transcription factors that promote expression of endogenous AR target genes and support androgen independent prostate cancer cell growth. Previous work has shown transcriptional activation unit 5 (TAU5) is necessary for ligand independent activity of the full length AR in low or no androgen conditions and that this activation is mediated by the WHTLF motif. The purpose of this study was to determine whether the TAU5 region was also important for regulating the constitutive activity of truncated AR variants. We generated deletion mutants of the AR variants and tested transcriptional activity by luciferase assay. We found that that the constitutive, ligand independent transcriptional activity of truncated AR variants was dependent on TAU5 for transcription. Surprisingly, we found that AR variants did not require WHTLF to mediate this ligand independent activity. We attempted to narrow down the region that may be important for variant transcriptional activity and found that deletion of amino acids 420-490 resulted in lower activity compared to AR 1/2/3 CE3. However, testing smaller regions of 420-490 did not elucidate a specific motif. These findings highlight TAU5 as a key AR domain through which AR activity could be inhibited for treatment of CRPC.
University of Minnesota M.S. thesis. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisors. Scott Dehm and Jim McCarthy. 1 computer file (PDF); viii, 45 pages.
Mutha, Sarita Kumari.
Role of transcriptional activation unit 5 (TAU5) in mediating transcriptional activity of androgen receptor splice variants.
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