Department of Microbiology and Physiological Systems; Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology; Department of Molecular, Cell and Cancer Biology; Department of Cell and Developmental Biology; Department of Pediatrics
Cancer Biology | Cell Biology | Developmental Biology
Members of the Dickkopf (Dkk) family of Wnt antagonists interrupt Wnt-induced receptor assembly and participate in axial patterning and cell fate determination. One family member, DKK3, does not block Wnt receptor activation. Loss of Dkk3 expression in cancer is associated with hyperproliferation and dysregulated ss-catenin signaling, and ectopic expression of Dkk3 halts cancer growth. The molecular events mediating the DKK3-dependent arrest of ss-catenin-driven cell proliferation in cancer cells are unknown. Here we report the identification of a new intracellular gene product originating from the Dkk3 locus. This Dkk3b transcript originates from a second transcriptional start site located in intron 2 of the Dkk3 gene. It is essential for early mouse development and is a newly recognized regulator of ss-catenin signaling and cell proliferation. Dkk3b interrupts nuclear translocation ss-catenin by capturing cytoplasmic, unphosphorylated ss-catenin in an extra-nuclear complex with ss-TrCP. These data reveal a new regulator of one of the most studied signal transduction pathways in metazoans and provides a novel, completely untapped therapeutic target for silencing the aberrant ss-catenin signaling that drives hyperproliferation in many cancers.
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Copyright: © 2017 Leonard et al. 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.
DOI of Published Version
PLoS One. 2017 Jul 24;12(7):e0181724. doi: 10.1371/journal.pone.0181724. eCollection 2017. Link to article on publisher's site
Leonard, Jack L.; Leonard, Deborah Marie; Wolfe, Scot A.; Liu, Jilin; Rivera-Perez, Jaime A.; Yang, Michelle; Leonard, Ryan T.; Johnson, Jacob P. S.; Kumar, Prashant; Liebmann, Kate L.; Tutto, Amanda A.; Mou, Zhongming; and Simin, Karl J., "The Dkk3 gene encodes a vital intracellular regulator of cell proliferation" (2017). Open Access Articles. 3202.
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This work is licensed under a Creative Commons Attribution 4.0 License.