PML nuclear bodies contribute to the basal expression of the mTOR inhibitor DDIT4.
PML nuclear bodies contribute to the basal expression of the mTOR inhibitor DDIT4.
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DOI：
10.1038/srep45038
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发表时间：
2017-03-23
影响因子：
4.6
通讯作者：
Dellaire G
中科院分区：
文献类型：
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作者：
Salsman J;Stathakis A;Parker E;Chung D;Anthes LE;Koskowich KL;Lahsaee S;Gaston D;Kukurba KR;Smith KS;Chute IC;Léger D;Frost LD;Montgomery SB;Lewis SM;Eskiw C;Dellaire G
早幼粒细胞白血病（PML）蛋白是癌症中经常丢失的PML核体（PML NBs）的重要组成部分。PML NBs通过对核蛋白的修饰来协调染色体区域，进而调节这些小体附近的基因。然而，很少发现与PML nb相关的基因。PML和PML NBs也可以调节mTOR和细胞命运决定，以响应细胞应激。我们现在证明，在U2OS细胞或tert永活的正常人类二倍体成纤维细胞中PML的缺失导致mTOR抑制剂DDIT4 （REDD1）的表达降低。DNA和RNA免疫fish显示PML NBs与活跃转录的DDIT4位点密切相关，暗示这些体参与调节基础DDIT4表达。虽然PML沉默确实降低了U2OS细胞对二甲双胍诱导的代谢应激的敏感性，但PML缺失并没有抑制二甲双胍、低氧样（CoCl2）或基因毒性应激时DDIT4的上调。对可公开获得的癌症数据的分析也揭示了PML和DDIT4在几种癌症类型（如肺癌、乳腺癌、前列腺癌）中的表达之间的显著相关性。因此，这些发现揭示了PML缺失可能通过基底DDIT4基因表达失调促进mTOR激活和癌症进展的新机制。
The promyelocytic leukemia (PML) protein is an essential component of PML nuclear bodies (PML NBs) frequently lost in cancer. PML NBs coordinate chromosomal regions via modification of nuclear proteins that in turn may regulate genes in the vicinity of these bodies. However, few PML NB-associated genes have been identified. PML and PML NBs can also regulate mTOR and cell fate decisions in response to cellular stresses. We now demonstrate that PML depletion in U2OS cells or TERT-immortalized normal human diploid fibroblasts results in decreased expression of the mTOR inhibitor DDIT4 (REDD1). DNA and RNA immuno-FISH reveal that PML NBs are closely associated with actively transcribed DDIT4 loci, implicating these bodies in regulation of basal DDIT4 expression. Although PML silencing did reduce the sensitivity of U2OS cells to metabolic stress induced by metformin, PML loss did not inhibit the upregulation of DDIT4 in response to metformin, hypoxia-like (CoCl2) or genotoxic stress. Analysis of publicly available cancer data also revealed a significant correlation between PML and DDIT4 expression in several cancer types (e.g. lung, breast, prostate). Thus, these findings uncover a novel mechanism by which PML loss may contribute to mTOR activation and cancer progression via dysregulation of basal DDIT4 gene expression.