全基因组 RNA 干扰筛选揭示了恶性神经胶质瘤中具有治疗意义的关键 CREB3L2-ATF5-MCL1 存活途径。

A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications.

机构信息

Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

出版信息

Nat Med. 2010 Jun;16(6):671-7. doi: 10.1038/nm.2158. Epub 2010 May 23.

DOI:10.1038/nm.2158

PMID:20495567

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2882506/

Abstract

Activating transcription factor-5 (ATF5) is highly expressed in malignant glioma and has a key role in promoting cell survival. Here we perform a genome-wide RNAi screen to identify transcriptional regulators of ATF5. Our results reveal an essential survival pathway in malignant glioma, whereby activation of a RAS-mitogen-activated protein kinase or phosphoinositide-3-kinase signaling cascade leads to induction of the transcription factor cAMP response element-binding protein-3-like-2 (CREB3L2), which directly activates ATF5 expression. ATF5, in turn, promotes survival by stimulating transcription of myeloid cell leukemia sequence-1 (MCL1), an antiapoptotic B cell leukemia-2 family member. Analysis of human malignant glioma samples indicates that ATF5 expression inversely correlates with disease prognosis. The RAF kinase inhibitor sorafenib suppresses ATF5 expression in glioma stem cells and inhibits malignant glioma growth in cell culture and mouse models. Our results demonstrate that ATF5 is essential in malignant glioma genesis and reveal that the ATF5-mediated survival pathway described here provides potential therapeutic targets for treatment of malignant glioma.

摘要

激活转录因子-5（ATF5）在恶性神经胶质瘤中高度表达，并且在促进细胞存活方面发挥关键作用。在这里，我们进行了全基因组 RNAi 筛选，以鉴定 ATF5 的转录调节因子。我们的结果揭示了恶性神经胶质瘤中的一个重要存活途径，即 RAS-有丝分裂原激活的蛋白激酶或磷酸肌醇 3-激酶信号级联的激活导致转录因子 cAMP 反应元件结合蛋白-3 样-2（CREB3L2）的诱导，其直接激活 ATF5 的表达。反过来，ATF5 通过刺激髓样细胞白血病序列-1（MCL1）的转录来促进存活，MCL1 是一种抗凋亡的 B 细胞白血病-2 家族成员。对人类恶性神经胶质瘤样本的分析表明，ATF5 的表达与疾病预后呈负相关。RAF 激酶抑制剂索拉非尼抑制神经胶质瘤干细胞中的 ATF5 表达，并抑制细胞培养和小鼠模型中的恶性神经胶质瘤生长。我们的结果表明 ATF5 在恶性神经胶质瘤发生中是必不可少的，并揭示了这里描述的 ATF5 介导的存活途径为恶性神经胶质瘤的治疗提供了潜在的治疗靶点。