Tumor suppressor BTG1 promotes PRMT1-mediated ATF4 function in response to cellular stress.
Tumor suppressor BTG1 promotes PRMT1-mediated ATF4 function in response to cellular stress.
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DOI：
10.18632/oncotarget.6519
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发表时间：
2016-01-19
期刊：
影响因子：
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通讯作者：
van Leeuwen FN
中科院分区：
文献类型：
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作者：
Yuniati L;van der Meer LT;Tijchon E;van Ingen Schenau D;van Emst L;Levers M;Palit SA;Rodenbach C;Poelmans G;Hoogerbrugge PM;Shan J;Kilberg MS;Scheijen B;van Leeuwen FN
癌细胞经常暴露在生理应激条件下，如缺氧和营养限制。逃避应激诱导的细胞凋亡是恶性细胞在不利条件下生存的机制之一。B细胞易位基因1 （BTG1）是一种肿瘤抑制因子，在急性淋巴细胞白血病中经常缺失，在弥漫性大B细胞淋巴瘤中反复突变。此外，低BTG1表达水平与几种实体瘤的不良预后有关。BTG1功能的丧失如何促进肿瘤进展尚不清楚。在这里，我们使用Btg1敲除小鼠，证明Btg1的缺失为应激条件下的原代小鼠胚胎成纤维细胞（mef）提供了生存优势。这种促进生存的作用涉及激活转录因子4 （ATF4）的调节，ATF4是细胞应激反应的关键介质。我们发现BTG1与ATF4相互作用，并通过招募蛋白精氨酸甲基转移酶PRMT1在精氨酸残基239上甲基化ATF4来正向调节其活性。我们进一步将这些发现扩展到B细胞祖细胞，通过表明Btg1表达的缺失增强了小鼠骨髓源性B细胞祖细胞的应激适应性。总之，我们已经确定BTG1/PRMT1复合物是ATF4介导的应激反应的新修饰剂。
Cancer cells are frequently exposed to physiological stress conditions such as hypoxia and nutrient limitation. Escape from stress-induced apoptosis is one of the mechanisms used by malignant cells to survive unfavorable conditions. B-cell Translocation Gene 1 (BTG1) is a tumor suppressor that is frequently deleted in acute lymphoblastic leukemia and recurrently mutated in diffuse large B cell lymphoma. Moreover, low BTG1 expression levels have been linked to poor outcome in several solid tumors. How loss of BTG1 function contributes to tumor progression is not well understood. Here, using Btg1 knockout mice, we demonstrate that loss of Btg1 provides a survival advantage to primary mouse embryonic fibroblasts (MEFs) under stress conditions. This pro-survival effect involves regulation of Activating Transcription Factor 4 (ATF4), a key mediator of cellular stress responses. We show that BTG1 interacts with ATF4 and positively modulates its activity by recruiting the protein arginine methyl transferase PRMT1 to methylate ATF4 on arginine residue 239. We further extend these findings to B-cell progenitors, by showing that loss of Btg1 expression enhances stress adaptation of mouse bone marrow-derived B cell progenitors. In conclusion, we have identified the BTG1/PRMT1 complex as a new modifier of ATF4 mediated stress responses.