Quantitative proteomics reveals that long non-coding RNA MALAT1 interacts with DBC1 to regulate p53 acetylation.
Quantitative proteomics reveals that long non-coding RNA MALAT1 interacts with DBC1 to regulate p53 acetylation.
复制标题
定量蛋白质组学揭示长非编码 RNA MALAT1 与 DBC1 相互作用调节 p53 乙酰化
DOI：
10.1093/nar/gkx600
复制
发表时间：
2017-09-29
影响因子：
14.9
通讯作者：
Zhang N
中科院分区：
文献类型：
--
作者：
Chen R;Liu Y;Zhuang H;Yang B;Hei K;Xiao M;Hou C;Gao H;Zhang X;Jia C;Li L;Li Y;Zhang N
摘要转移相关肺腺癌转录本1(MALAT1)是一种广泛表达的lncRNA，参与多种细胞过程。为了进一步阐明潜在的分子机制，我们采用了高通量策略，通过结合RNA下拉、定量蛋白质组学、生物信息学和实验验证来表征MALAT1的相互作用蛋白质。我们的方法确定了127个潜在的MALAT1相互作用蛋白，并建立了一个由788个连接组成的高度连接的MALAT1相互作用组网。基因本体注释和网络分析表明，MALAT1高度参与了五个生物学过程：RNA加工、基因转录、核糖体蛋白、蛋白质降解和代谢调节。通过RNA下拉和RNA免疫沉淀验证了MALAT1与乳腺癌耗竭细胞1(DBC1)之间的相互作用。进一步的机制研究表明，MALAT1结合与Sirtuin1(SIRT1)和DBC1之间的相互作用竞争，从而释放SIRT1并增强其脱乙酰基活性。因此，P53的去乙酰化减少了其下游靶基因的转录，促进了细胞增殖，抑制了细胞凋亡。我们的结果揭示了MALAT1通过lncRNA-蛋白质相互作用调节P53活性的新机制。
Abstract Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a broadly expressed lncRNA involved in many aspects of cellular processes. To further delineate the underlying molecular mechanism, we employed a high-throughput strategy to characterize the interacting proteins of MALAT1 by combining RNA pull-down, quantitative proteomics, bioinformatics, and experimental validation. Our approach identified 127 potential MALAT1-interacting proteins and established a highly connected MALAT1 interactome network consisting of 788 connections. Gene ontology annotation and network analysis showed that MALAT1 was highly involved in five biological processes: RNA processing; gene transcription; ribosomal proteins; protein degradation; and metabolism regulation. The interaction between MALAT1 and depleted in breast cancer 1 (DBC1) was validated using RNA pull-down and RNA immunoprecipitation. Further mechanistic studies reveal that MALAT1 binding competes with the interaction between sirtuin1 (SIRT1) and DBC1, which then releases SIRT1 and enhances its deacetylation activity. Consequently, the deacetylation of p53 reduces the transcription of a spectrum of its downstream target genes, promotes cell proliferation and inhibits cell apoptosis. Our results uncover a novel mechanism by which MALAT1 regulates the activity of p53 through the lncRNA–protein interaction.
登录
查看更多内容
影响因子：
64.5
作者：
Huarte M;Guttman M;Feldser D;Garber M;Koziol MJ;Kenzelmann-Broz D;Khalil AM;Zuk O;Amit I;Rabani M;Attardi LD;Regev A;Lander ES;Jacks T;Rinn JL
通讯作者：
Rinn JL
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1083/jcb.201601024
发表时间：
2016-07-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mannen T;Yamashita S;Tomita K;Goshima N;Hirose T
通讯作者：
Hirose T
乳腺癌 1 中删除了一种新型雄激素受体 (AR) 共激活剂，可促进 AR DNA 结合活性
影响因子：
4.8
作者：
Fu, Junjiang;Jiang, Jun;Wong, Jiemin
通讯作者：
Wong, Jiemin
影响因子：
8
作者：
Lin, R.;Maeda, S.;Edgington, T. S.
通讯作者：
Edgington, T. S.