Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB.
Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB.
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DOI：
10.1371/journal.pgen.1003368
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发表时间：
2013-03
期刊：
影响因子：
4.5
通讯作者：
Prasanth KV
中科院分区：
文献类型：
--
作者：
Tripathi V;Shen Z;Chakraborty A;Giri S;Freier SM;Wu X;Zhang Y;Gorospe M;Prasanth SG;Lal A;Prasanth KV
长的非编码MALAT1 RNA在癌症组织中上调，其表达上调与过度增殖有关，但其潜在机制尚不清楚。我们证明了MALAT1水平在正常的细胞周期进程中是被调节的。对正常人二倍体成纤维细胞的全基因组转录组分析表明，MALAT1调节细胞周期基因的表达，是G1/S和有丝分裂进程所必需的。MALAT1的缺失导致P53及其靶基因的激活。在MALAT1缺失的细胞中观察到的细胞周期缺陷对P53水平敏感，表明P53是MALAT1活性的主要下游调节因子。此外，由于剪接因子与B-MYB Pre-mRNA结合的改变和异常的选择性剪接，MALAT1缺失的细胞显示出参与G2/M进展的致癌转录因子B-MYB(Mybl2)的表达减少。在人类细胞中，MALAT1通过调节细胞周期调节转录因子的表达和/或前mRNA的处理来促进细胞增殖。这些发现为MALAT1在调节细胞增殖中的作用提供了机械性的见解。哺乳动物基因组编码大量的非蛋白质编码的长RNA(LncRNAs)。这些LncRNAs被认为调节关键的生物学过程(包括细胞的增殖和分化)，而这些基因的异常表达与癌症有关。然而，这些LncRNA中只有一小部分在生物学或疾病过程中得到了功能验证。MALAT1是一种丰富的核内滞留的lncRNA，在多种肿瘤中过表达，其高表达与肿瘤的过度增殖和转移有关。然而，这种放松管制背后的潜在机制及其与癌症的关联却知之甚少。在这里，我们确定了MALAT1在细胞周期途径中的作用，并提出了其在正常细胞周期进程中发挥作用的分子机制。MALAT1的RNA水平受到不同的调控，对正常的细胞周期进程至关重要。MALAT1的缺失导致细胞周期停滞，细胞增殖显著降低，同时导致P53及其靶基因的激活。此外，细胞中MALAT1的准确水平对于参与G2/M进展的致癌转录因子B-MYB的表达和活性至关重要。我们的数据表明，与癌症相关的MALAT1 RNA通过调节细胞周期调节转录因子的表达和/或前mRNA处理来调节细胞增殖。
The long noncoding MALAT1 RNA is upregulated in cancer tissues and its elevated expression is associated with hyper-proliferation, but the underlying mechanism is poorly understood. We demonstrate that MALAT1 levels are regulated during normal cell cycle progression. Genome-wide transcriptome analyses in normal human diploid fibroblasts reveal that MALAT1 modulates the expression of cell cycle genes and is required for G1/S and mitotic progression. Depletion of MALAT1 leads to activation of p53 and its target genes. The cell cycle defects observed in MALAT1-depleted cells are sensitive to p53 levels, indicating that p53 is a major downstream mediator of MALAT1 activity. Furthermore, MALAT1-depleted cells display reduced expression of B-MYB (Mybl2), an oncogenic transcription factor involved in G2/M progression, due to altered binding of splicing factors on B-MYB pre-mRNA and aberrant alternative splicing. In human cells, MALAT1 promotes cellular proliferation by modulating the expression and/or pre-mRNA processing of cell cycle–regulated transcription factors. These findings provide mechanistic insights on the role of MALAT1 in regulating cellular proliferation. The mammalian genome encodes large number of long non protein-coding RNAs (lncRNAs). These lncRNAs are suggested to regulate key biological processes (including cellular proliferation and differentiation), and aberrant expression of these is associated with cancer. However, only a few of these lncRNAs have been functionally validated in biological or disease processes. MALAT1, an abundant nuclear-retained lncRNA, is overexpressed in several cancers, and its elevated expression has been associated with hyper-proliferation and metastasis. However, the underlying mechanism behind this deregulation and its association with cancer is poorly understood. Here, we establish the role of MALAT1 in the cell cycle pathway and propose the molecular mechanism of its function during normal cell cycle progression. MALAT1 RNA levels are differentially regulated and critical for normal cell cycle progression. Depletion of MALAT1 results in cell cycle arrest with significantly reduced cellular proliferation, simultaneously leading to activation of p53 and its target genes. Further, the accurate levels of MALAT1 in the cell are extremely crucial for expression and activity of the oncogenic transcription factor B-MYB, which is involved in G2/M progression. Our data indicates that the cancer-associated MALAT1 RNA regulates cellular proliferation by modulating the expression and/or pre-mRNA processing of cell cycle–regulated transcription factors.
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影响因子：
4.5
作者：
Burd CE;Jeck WR;Liu Y;Sanoff HK;Wang Z;Sharpless NE
通讯作者：
Sharpless NE
影响因子：
3.3
作者：
Freund A;Laberge RM;Demaria M;Campisi J
通讯作者：
Campisi J
影响因子：
11.2
作者：
Aguilo F;Zhou MM;Walsh MJ
通讯作者：
Walsh MJ
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1016/j.bbagrm.2012.03.008
发表时间：
2012-08-01
影响因子：
4.7
作者：
Down, Christin F.;Millour, Julie;Watson, Roger J.
通讯作者：
Watson, Roger J.