Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition.
Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition.
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DOI：
10.1016/j.celrep.2014.08.025
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发表时间：
2014-09-25
期刊：
影响因子：
8.8
通讯作者：
Lowe SW
中科院分区：
文献类型：
--
作者：
Bolden JE;Tasdemir N;Dow LE;van Es JH;Wilkinson JE;Zhao Z;Clevers H;Lowe SW
BET家族蛋白是癌症和炎症的新治疗靶点，代表了第一个针对小分子抑制剂的染色质读取器。第一代BET抑制剂已在临床前模型中显示出治疗效果，但在正常组织中持续BET蛋白抑制的后果仍不清楚。利用可诱导和可逆的转基因RNAi小鼠模型，我们发现在成年动物中，对BET蛋白Brd4的强烈抑制在多个组织中具有显著的作用。brd4缺失小鼠表现出可逆性表皮增生、脱发、细胞多样性降低和小肠干细胞衰竭。此外，Brd4抑制的肠道对器官应激敏感，并在照射后表现出再生受损，这表明Brd4抑制和某些细胞毒性治疗同时进行可能会诱导不良的协同效应。这些发现为了解Brd4在正常组织中的功能提供了重要的见解，重要的是，预测了与有效和持续的BET蛋白抑制相关的几种潜在结果。
BET family proteins are novel therapeutic targets for cancer and inflammation and represent the first chromatin readers against which small-molecule inhibitors have been developed. First-generation BET inhibitors have shown therapeutic efficacy in preclinical models, but the consequences of sustained BET protein inhibition in normal tissues remain poorly characterized. Using an inducible and reversible transgenic RNAi mouse model, we show that strong suppression of the BET protein Brd4 in adult animals has dramatic effects in multiple tissues. Brd4-depleted mice display reversible epidermal hyperplasia, alopecia, and decreased cellular diversity and stem cell depletion in the small intestine. Furthermore, Brd4-suppressed intestines are sensitive to organ stress and show impaired regeneration following irradiation, suggesting that concurrent Brd4 suppression and certain cytotoxic therapies may induce undesirable synergistic effects. These findings provide important insight into Brd4 function in normal tissues and, importantly, predict several potential outcomes associated with potent and sustained BET protein inhibition.
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影响因子：
64.5
作者：
Matzuk MM;McKeown MR;Filippakopoulos P;Li Q;Ma L;Agno JE;Lemieux ME;Picaud S;Yu RN;Qi J;Knapp S;Bradner JE
通讯作者：
Bradner JE
选择性抑制BET溴结构域。
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