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The Dkk3 gene encodes a vital intracellular regulator of cell proliferation

Jack L Leonard1, Deborah M Leonard2, Scot A Wolfe3,4

  • 1Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

Plos One
|July 25, 2017
PubMed

Insights

Researchers discovered a new gene product, Dkk3b, that regulates beta-catenin signaling and cell proliferation. This finding offers a potential new therapeutic target for cancers driven by aberrant beta-catenin signaling.

Area of Science:

  • Molecular biology
  • Developmental biology
  • Cancer biology

Background:

  • Dickkopf (Dkk) proteins are Wnt antagonists involved in development.
  • DKK3 is a member of the Dkk family, but its role in cancer is complex and not fully understood.
  • Loss of DKK3 expression in cancer correlates with hyperproliferation and aberrant beta-catenin signaling.

Purpose of the Study:

  • To identify the molecular mechanisms underlying DKK3's role in arresting beta-catenin-driven cancer cell proliferation.
  • To characterize a newly identified gene product from the Dkk3 locus.

Main Methods:

  • Identification and characterization of a novel transcript (Dkk3b) from the Dkk3 locus.
  • Analysis of Dkk3b's role in early mouse development.
  • Investigation of Dkk3b's mechanism of action on beta-catenin signaling.

Main Results:

  • A new intracellular gene product, Dkk3b, originates from a second transcriptional start site within the Dkk3 gene.
  • Dkk3b is essential for early mouse development.
  • Dkk3b regulates beta-catenin signaling and cell proliferation by interrupting nuclear translocation of beta-catenin.
  • Dkk3b captures cytoplasmic beta-catenin in an extra-nuclear complex with beta-TrCP.

Conclusions:

  • Dkk3b is a novel regulator of beta-catenin signaling and cell proliferation.
  • Dkk3b's mechanism involves preventing nuclear translocation of beta-catenin.
  • Dkk3b represents a new therapeutic target for silencing aberrant beta-catenin signaling in cancer.

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