The selective activation of p53 target genes regulated by SMYD2 in BIX-01294 induced autophagy-related cell death.
The selective activation of p53 target genes regulated by SMYD2 in BIX-01294 induced autophagy-related cell death.
复制标题
DOI：
10.1371/journal.pone.0116782
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Wu M
中科院分区：
文献类型：
--
作者：
Fan JD;Lei PJ;Zheng JY;Wang X;Li S;Liu H;He YL;Wang ZN;Wei G;Zhang X;Li LY;Wu M
转录调控是调控自噬的关键机制之一。H3 K9甲基化抑制剂激活LC 3B以及其他自噬相关基因的表达，并促进自噬过程。然而，由核因子调控的自噬的详细机制仍然难以捉摸。在这项研究中，我们对SMYD 2-/-细胞进行了药物筛选，发现SMYD 2缺陷增强了组蛋白H3 K9甲基化抑制剂BIX 01294诱导的细胞死亡。BIX-01294诱导LC 3 II的积累和自噬相关的细胞死亡，但不诱导半胱天冬酶依赖性细胞凋亡。我们分析了用BIX-01294处理后的整体基因表达模式，并与雷帕霉素进行了比较。BIX-01294选择性激活p53信号转导的下游基因，如p21和DOR，但不激活p53靶基因-一种典型的诱导凋亡的p53靶基因。BIX-01294还诱导其他自噬相关基因，如ATG 4A和ATG 9A。SMYD 2是p53的甲基转移酶，并调节其转录活性。其缺陷通过转录促进p53靶基因的表达增强BIX-01294诱导的自噬相关细胞死亡。综上所述，我们的数据表明BIX-01294诱导自噬相关的细胞死亡，并选择性激活p53靶基因，这是由SMYD 2甲基转移酶抑制。
Transcription regulation emerged to be one of the key mechanisms in regulating autophagy. Inhibitors of H3K9 methylation activates the expression of LC3B, as well as other autophagy-related genes, and promotes autophagy process. However, the detailed mechanisms of autophagy regulated by nuclear factors remain elusive. In this study, we performed a drug screen of SMYD2-/- cells and discovered that SMYD2 deficiency enhanced the cell death induced by BIX01294, an inhibitor of histone H3K9 methylation. BIX-01294 induces accumulation of LC3 II and autophagy-related cell death, but not caspase-dependent apoptosis. We profiled the global gene expression pattern after treatment with BIX-01294, in comparison with rapamycin. BIX-01294 selectively activates the downstream genes of p53 signaling, such as p21 and DOR, but not PUMA, a typical p53 target gene inducing apoptosis. BIX-01294 also induces other autophagy-related genes, such as ATG4A and ATG9A. SMYD2 is a methyltransferase for p53 and regulates its transcription activity. Its deficiency enhances the BIX-01294-induced autophagy-related cell death through transcriptionally promoting the expression of p53 target genes. Taken together, our data suggest BIX-01294 induces autophagy-related cell death and selectively activates p53 target genes, which is repressed by SMYD2 methyltransferase.
登录
查看更多内容
影响因子：
3.7
作者：
Diehl F;Brown MA;van Amerongen MJ;Novoyatleva T;Wietelmann A;Harriss J;Ferrazzi F;Böttger T;Harvey RP;Tucker PW;Engel FB
通讯作者：
Engel FB
影响因子：
16
作者：
Kubicek, Stefan;O'Sullivan, Roderick J.;Jenuwein, Thomas
通讯作者：
Jenuwein, Thomas
影响因子：
6.6
作者：
Culmes, Mihaela;Eckstein, Hans-Henning;Pelisek, Jaroslav
通讯作者：
Pelisek, Jaroslav
影响因子：
64.5
作者：
Green DR;Levine B
通讯作者：
Levine B
影响因子：
3.5
作者：
Leinhart K;Brown M
通讯作者：
Brown M