REDD1/DDIT4-independent mTORC1 inhibition and apoptosis by glucocorticoids in thymocytes.
REDD1/DDIT4-independent mTORC1 inhibition and apoptosis by glucocorticoids in thymocytes.
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DOI：
10.1158/1541-7786.mcr-13-0625
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发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Brugarolas J
中科院分区：
文献类型：
--
作者：
Wolff NC;McKay RM;Brugarolas J
糖皮质激素(GCs)可诱导淋巴细胞凋亡，常用于治疗血液系统恶性肿瘤。然而，它们也与显著的不良反应有关，其分子作用机制尚不完全清楚。GC治疗可诱导发育和DNA损伤反应中调节的mTORC1抑制因子1(Redd1)的表达，也称为DNA损伤诱导转录因子4(DDIT4)，抑制mTORC1可以区分GC敏感细胞和GC耐药细胞。有趣的是，在对GC耐药的ALL细胞中，Redd1的诱导受到损害，使用雷帕霉素抑制mTORC1可恢复GC的敏感性。这些数据表明，Redd1在所有细胞对糖皮质激素的反应中可能是必不可少的。为了进一步研究Redd1的作用，我们评估了糖皮质激素对野生型和Redd1缺陷小鼠的原代胸腺细胞的影响。GC介导的细胞凋亡可被GC受体拮抗剂和转录抑制物阻断，从而干扰Redd1的诱导和mTORC1的抑制。然而，Redd1消融对GC诱导的胸腺细胞mTORC1抑制和细胞凋亡无影响。总体而言，这些数据不仅显示了GC处理后下游信号的上下文差异，而且还提供了对Redd1作用的更好的机制理解。
Glucocorticoids (GCs) induce apoptosis in lymphocytes and are commonly used to treat hematologic malignancies. However, they are also associated with significant adverse effects and their molecular mechanism of action is not fully understood. GC treatment induces expression of the mTORC1 inhibitor Regulated in Development and DNA Damage Response 1 (REDD1), also known as DNA-Damage Inducible Transcript 4 (DDIT4), and mTORC1 inhibition may distinguish GC-sensitive from GC-resistant acute lymphoblastic leukemia (ALL) cells. Interestingly, REDD1 induction was impaired in GC-resistant ALL cells and inhibition of mTORC1 using rapamycin restored GC sensitivity. These data suggest that REDD1 may be essential for the response of ALL cells to glucocorticoids. To further investigate the role of REDD1, we evaluated the effects of glucocorticoids on primary thymocytes from wild-type and REDD1-deficient mice. GC-mediated apoptosis was blocked by a GC receptor antagonist and by an inhibitor of transcription, which interfered with REDD1 induction and mTORC1 inhibition. However, REDD1 ablation had no effect on GC-induced mTORC1 inhibition and apoptosis in thymocytes ex vivo. Overall, these data not only demonstrate the contextual differences of downstream signaling following GC treatment but also provide a better mechanistic understanding of the role of REDD1.
白血病细胞和原发性胸腺细胞的基因表达分析预测了对糖皮质激素凋亡敏感性的特征。
影响因子：
5.8
作者：
Miller, Aaron L.;Komak, Spogmai;Webb, M. Scott;Leiter, Edward H.;Thompson, E. Brad
通讯作者：
Thompson, E. Brad