PRMT1 promotes the tumor suppressor function of p14(ARF) and is indicative for pancreatic cancer prognosis.
PRMT1 promotes the tumor suppressor function of p14(ARF) and is indicative for pancreatic cancer prognosis.
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PRMT1 促进 p14(ARF) 的肿瘤抑制功能，并指示胰腺癌的预后。
DOI：
10.15252/embj.2020106777
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发表时间：
2021-07-01
期刊：
影响因子：
--
通讯作者：
Bauer UM
中科院分区：
文献类型：
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作者：
Repenning A;Happel D;Bouchard C;Meixner M;Verel-Yilmaz Y;Raifer H;Holembowski L;Krause E;Kremmer E;Feederle R;Keber CU;Lohoff M;Slater EP;Bartsch DK;Bauer UM
P14ARF蛋白是一种众所周知的P53依赖和非P53非依赖性肿瘤抑制活性的调节因子。在非应激细胞中，p14ARF主要滞留在核仁中，与其核仁相互作用伙伴NPM结合。在基因毒性应激下，p14ARF立即重新分布到核质中，在那里它促进了细胞周期停滞和细胞凋亡的激活。在这里，我们确定p14ARF是PRMT1(蛋白质精氨酸甲基转移酶1)的一个新的相互作用伙伴和底物。PRMT1甲基化p14ARF C末端核/核仁定位序列(NLS/NOLS)中的几个精氨酸残基。在没有细胞应激的情况下，这些精氨酸对p14ARF的核仁定位至关重要。基因毒性应激导致PRMT1和p14ARF之间的相互作用增强，并伴随着p14ARF的精氨酸甲基化。依赖于PRMT1的NLS/NOLS甲基化促进p14ARF从NPM释放和核仁隔离，从而导致非p53依赖的细胞凋亡。这种PRMT1-p14ARF的协同作用与肿瘤相关，并可作为预测胰腺导管腺癌的预后和胰腺肿瘤细胞化疗反应的指标。我们的数据显示，PRMT1介导的精氨酸甲基化是p14ARF应激诱导的肿瘤抑制功能的重要触发因素。核/核仁定位序列中的精氨酸甲基化通过p14ARF调节细胞内的再分布和促进p53非依赖性的细胞凋亡。
The p14ARF protein is a well‐known regulator of p53‐dependent and p53‐independent tumor‐suppressive activities. In unstressed cells, p14ARF is predominantly sequestered in the nucleoli, bound to its nucleolar interaction partner NPM. Upon genotoxic stress, p14ARF undergoes an immediate redistribution to the nucleo‐ and cytoplasm, where it promotes activation of cell cycle arrest and apoptosis. Here, we identify p14ARF as a novel interaction partner and substrate of PRMT1 (protein arginine methyltransferase 1). PRMT1 methylates several arginine residues in the C‐terminal nuclear/nucleolar localization sequence (NLS/NoLS) of p14ARF. In the absence of cellular stress, these arginines are crucial for nucleolar localization of p14ARF. Genotoxic stress causes augmented interaction between PRMT1 and p14ARF, accompanied by arginine methylation of p14ARF. PRMT1‐dependent NLS/NoLS methylation promotes the release of p14ARF from NPM and nucleolar sequestration, subsequently leading to p53‐independent apoptosis. This PRMT1‐p14ARF cooperation is cancer‐relevant and indicative for PDAC (pancreatic ductal adenocarcinoma) prognosis and chemotherapy response of pancreatic tumor cells. Our data reveal that PRMT1‐mediated arginine methylation is an important trigger for p14ARF’s stress‐induced tumor‐suppressive function. Arginine methylation in the nuclear/nucleolar localization sequence regulates intracellular redistribution and promotion of p53‐independent apoptosis by of p14ARF.