Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG Journal Article
| Authors: | Wasmuth, E. V.; Hoover, E. A.; Antar, A.; Klinge, S.; Chen, Y.; Sawyers, C. L. |
| Article Title: | Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG |
| Abstract: | The androgen receptor (AR) is a type I nuclear hormone receptor and the primary drug target in prostate cancer due to its role as a lineage survival factor in prostate luminal epithelium. In prostate cancer, the AR cistrome is reprogrammed relative to normal prostate epithelium and particularly in cancers driven by oncogenic ETS fusion genes. The molecular basis for this change has remained elusive. Using purified proteins, we report a minimal cell-free system that demonstrates interdomain cooperativity between the ligand (LBD) and DNA binding domains (DBD) of AR, and its autoinhibition by the N terminus of AR. Furthermore, we identify ERG as a cofactor that activates AR's ability to bind DNA in both high and lower affinity contexts through direct interaction within a newly identified AR-interacting motif (AIM) in the ETS domain, independent of ERG's own DNA binding ability. Finally, we present evidence that this interaction is conserved among ETS factors whose expression is altered in prostate cancer. Our work highlights, at a biochemical level, how tumor-initiating ETS trans-locations result in reprogramming of the AR cistrome. © 2020 National Academy of Sciences. All rights reserved. |
| Keywords: | controlled study; protein domain; protein motif; prostate cancer; amino terminal sequence; transcription factor erg; transactivation; androgen receptor; antiandrogen; conformational transition; dna binding; cell free system; dna template; priority journal; article; ligand binding domain; dna binding domain; ets domain; cistrome; androgen receptor interacting motif |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 117 |
| Issue: | 15 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2020-04-14 |
| Start Page: | 8584 |
| End Page: | 8592 |
| Language: | English |
| DOI: | 10.1073/pnas.1922159117 |
| PUBMED: | 32220959 |
| PROVIDER: | scopus |
| PMCID: | PMC7165421 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2020 -- Source: Scopus |
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