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Redirecting RNA splicing by SMAD3 turns TGF-β into a tumor promoter

Veenu Tripathi1, Ying E Zhang1

  • 1Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute , Bethesda, MD, USA.

Molecular & Cellular Oncology
|February 16, 2017
PubMed

Insights

Transforming growth factor beta (TGF-β) normally inhibits cell growth but promotes cancer when secreted by tumors. A newly discovered SMAD3-PCBP1 complex controls this switch by altering pre-mRNA splicing.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Transforming growth factor beta (TGF-β) paradoxically inhibits normal epithelial cell growth while promoting solid tumor progression.
  • The dual role of TGF-β in cancer remains incompletely understood at the molecular level.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying TGF-β's switch from a tumor suppressor to a tumor promoter.
  • To investigate the role of protein complexes in regulating gene expression in cancer.

Main Methods:

  • Investigated the interaction between SMAD3 and PCBP1.
  • Characterized the RNA-binding properties of the SMAD3-PCBP1 complex.
  • Analyzed the impact of this complex on pre-mRNA splicing patterns.

Main Results:

  • Discovered a novel complex formed by SMAD3 and PCBP1 with direct RNA-binding capabilities.
  • Demonstrated that the SMAD3-PCBP1 complex directly influences pre-mRNA splicing.
  • Identified this complex as a key regulator in the context of TGF-β signaling in cancer.

Conclusions:

  • The SMAD3-PCBP1 complex is a critical mediator of TGF-β's pro-tumorigenic effects.
  • Regulation of pre-mRNA splicing by the SMAD3-PCBP1 complex is a key mechanism driving cancer progression.
  • Targeting this complex may offer new therapeutic strategies for solid tumors.
Keywords:
Alternative splicingEMTPCBP1SMAD3TGF-βmetastasis

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