作者
Omer Gilan, Inmaculada Rioja, Kathy Knezevic, Matthew J Bell, Miriam M Yeung, Nicola R Harker, Enid YN Lam, Chun-wa Chung, Paul Bamborough, Massimo Petretich, Marjeta Urh, Stephen J Atkinson, Anna K Bassil, Emma J Roberts, Dane Vassiliadis, Marian L Burr, Alex GS Preston, Christopher Wellaway, Thilo Werner, James R Gray, Anne-Marie Michon, Thomas Gobbetti, Vinod Kumar, Peter E Soden, Andrea Haynes, Johanna Vappiani, David F Tough, Simon Taylor, Sarah-Jane Dawson, Marcus Bantscheff, Matthew Lindon, Gerard Drewes, Emmanuel H Demont, Danette L Daniels, Paola Grandi, Rab K Prinjha, Mark A Dawson
发表日期
2020/4/24
期刊
Science
卷号
368
期号
6489
页码范围
387-394
出版商
American Association for the Advancement of Science
简介
The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of …
学术搜索中的文章
O Gilan, I Rioja, K Knezevic, MJ Bell, MM Yeung… - Science, 2020