Saenz G Jonatan, Hovanessian Rebeka, Gisis Andrew D, Medh Rheem D
Department of Biology, California State University Northridge, Northridge, CA 91330-8303, USA.
Biochem Biophys Res Commun. 2015 Aug 7;463(4):1291-6. doi: 10.1016/j.bbrc.2015.06.106. Epub 2015 Jun 20.
Glucocorticoids (GCs) are known to induce apoptosis of leukemia cells via gene regulatory changes affecting key pro-and anti-apoptotic genes. Three genes previously implicated in GC-evoked apoptosis in the CEM human T-cell leukemia model, RCAN1, E4BP4 and BIM, were studied in a panel of human lymphoid and myeloid leukemia cell lines. Of the two RCAN1 transcripts, the synthetic GC Dexamethasone (Dex) selectively upregulates RCAN1-1, but not RCAN1-4, in GC-susceptible Sup-B15, RS4;11, Kasumi-1 cells but not in GC-resistant Sup T1 and Loucy cells. E4BP4 and BIM regulation correlated with that of RCAN1-1. A putative GRE and four EBPREs were identified within 1500bp upstream from the transcription start site of RCAN1-1. GC-refractory CEM C1-15 cells sensitized to GC-evoked apoptosis by ectopic E4BP4 expression, CEM C1-15mE#3, showed restored RCAN1-1 upregulation, suggesting that RCAN1-1 is a downstream target of E4BP4. A model for coordinated regulation of RCAN1-1, E4BP4 and BIM, and their role in GC-evoked apoptosis is proposed.
已知糖皮质激素（GCs）通过影响关键促凋亡和抗凋亡基因的基因调控变化来诱导白血病细胞凋亡。在一组人类淋巴和髓系白血病细胞系中研究了先前在CEM人T细胞白血病模型中与GC诱导凋亡有关的三个基因，即RCAN1、E4BP4和BIM。在两种RCAN1转录本中，合成糖皮质激素地塞米松（Dex）在对GC敏感的Sup-B15、RS4;11、Kasumi-1细胞中选择性上调RCAN1-1，而不是RCAN1-4，但在对GC耐药的Sup T1和Loucy细胞中则不然。E4BP4和BIM的调控与RCAN1-1的调控相关。在RCAN1-1转录起始位点上游1500bp内鉴定出一个假定的糖皮质激素反应元件（GRE）和四个E盒结合蛋白4反应元件（EBPRE）。对GC诱导的凋亡敏感的GC难治性CEM C1-15细胞，即异位表达E4BP4的CEM C1-15mE#3，显示出恢复的RCAN1-1上调，这表明RCAN1-1是E4BP4的下游靶点。本文提出了一个关于RCAN1-1、E4BP4和BIM协同调控及其在GC诱导凋亡中的作用的模型。
