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Direct Regulation of Alternative Splicing by SMAD3 through PCBP1 Is Essential to the Tumor-Promoting Role of TGF-beta

  1. Author:
    Tripathi, V.
    Sixt, K. M.
    Gao, S.
    Xu, X.
    Huang, J.
    Weigert, R.
    Zhou, M.
    Zhang, Y. E.

  2. Author Address

    Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Laboratory of Protein Characterization, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: zhangyin@mail.nih.gov.
    1. Year: 2016
    2. Date: 4-Oct
    3. Epub Date: 10/18/2016
  2. Journal: Molecular Cell
    1. 64
    2. 3
    3. Pages: 549-564
  4. Type of Article: Article
  5. ISSN: 1097-2765
  1. Abstract:

    In advanced stages of cancers, TGF-beta promotes tumor progression in conjunction with inputs from receptor tyrosine kinase pathways. However, mechanisms that underpin the signaling cooperation and convert TGF-beta from a potent growth inhibitor to a tumor promoter are not fully understood. We report here that TGF-beta directly regulates alternative splicing of cancer stem cell marker CD44 through a phosphorylated T179 of SMAD3-mediated interaction with RNA-binding protein PCBP1. We show that TGF-beta and EGF respectively induce SMAD3 and PCBP1 to colocalize in SC35-positive nuclear speckles, and the two proteins interact in the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly in favor of expressing the mesenchymal isoform CD44s over the epithelial isoform CD44E. We further show that the SMAD3-mediated alternative splicing is essential to the tumor-promoting role of TGF-beta and has a global influence on protein products of genes instrumental to epithelial-to-mesenchymal transition and metastasis.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.molcel.2016.09.013
  3. PMID: 27746021
  4. View record in Web of Science®
  5. WOS: 000389515300013

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