Allosteric alterations in the androgen receptor and activity in prostate cancer

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   Figure 1

   Schematic representation showing AR gene structure of AR-FL and AR-Vs. (A) AR-FL protein (GenBank accession no. NP_000035.2) is translated from the message produced from canonical splicing to possess four major domains as well as definable functional motifs (refer to the text for details). The matched colors were used for the exons in the genome as well as transcript and the corresponding protein regions. The positions of stop codon are indicated by arrow heads. Exon 9 is defined as the exon located far downstream of exon 8. As exemplified by the transcript (GenBank accession No. NM_000044.3), the eighth exon (E8) corresponds to the unspliced long exon covering exon 8, intron 8 and exon 9. Furthermore, defined structural units are depicted along the protein structure of AR-FL (see text): Skipping of the specified exons leads to loss of the corresponding units. (B) The transcript and protein structures of representative AR-Vs are drawn. Truncated variants (e.g., AR-V7) are produced by incorporating CEs, whereas inclusion/exclusion of specified exons generates a variety of exon-skipping variants. Skipping the specified exons results in the frameshift, by which the respective AR-Vs have their unique C-terminal sequences (closed rectangles). Note that ARv5es, v6es, v56es and v7es are newly discovered AR-Vs through construction of splicing landscapes of AR in mCRPC. AR45 lacks the entire NTD by missing exon 1 through the use of alternative promoter.
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   Figure 2

   Three distinct AR GSR driving to synthesis of ARv567es. 9-kb inversion and deletion AR exons 5–7 were detected in human xenografts LuCaP 136 and LuCaP 86.2, respectively. The cells undergoing these GSR exclusively express ARv567es. mPCa cells in the rapid autopsy patient C-6 have the unique AR GSR after a multi-step rearrangement (i.e., combined duplication and deletion events), leading to simultaneous deletion of AR exons 5 and 6. The resulting AR gene has the newly structured intron 7, which is mostly composed of the portion of original intron 5 (gray line). Owing to the presence of intact exon 7, splicing of exon 4–8 to skip exon 7 appears to be the prerequisite step to produce ARv567es in this situation.

• © 2017 Society for Endocrinology