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      Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB

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          Abstract

          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.

          Author Summary

          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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          Author and article information

          Contributors
          Role: Editor
          Journal
          PLoS Genet
          PLoS Genet
          plos
          plosgen
          PLoS Genetics
          Public Library of Science (San Francisco, USA )
          1553-7390
          1553-7404
          March 2013
          March 2013
          21 March 2013
          : 9
          : 3
          : e1003368
          Affiliations
          [1 ]Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
          [2 ]ISIS Pharmaceuticals, Carlsbad, California, United States of America
          [3 ]Laboratory of Molecular Technology, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America
          [4 ]Research Resources Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
          [5 ]Laboratory of Molecular Biology and Immunology, National Institute of Aging, National Institutes of Health, Baltimore, Maryland, United States of America
          [6 ]Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
          Fred Hutchinson Cancer Research Center, United States of America
          Author notes

          SMF is an employee of Isis Pharmaceutical, receives salary from the company, and holds stock options. The other authors have declared that no competing interests exist.

          Conceived and designed the experiments: VT KVP. Performed the experiments: VT ZS SG AC XW YZ. Analyzed the data: VT KVP XW YZ MG AL SGP. Contributed reagents/materials/analysis tools: SMF. Wrote the paper: KVP VT.

          Article
          PGENETICS-D-12-02155
          10.1371/journal.pgen.1003368
          3605280
          23555285
          b816143e-00a3-48b5-b417-4d37ad3a214b
          Copyright @ 2013

          This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

          History
          : 24 August 2012
          : 21 January 2013
          Page count
          Pages: 18
          Funding
          This work was supported by grants from American Cancer Society (RSG-11-174-01-RMC) and NIH GM088252 to KVP and by grants NSF0843604 and NIH GM099669 to SGP. MG and YZ are supported by the NIA-IRP, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
          Categories
          Research Article
          Biology
          Biochemistry
          Genetics
          Molecular Cell Biology
          Medicine
          Oncology

          Genetics
          Genetics

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