Leonard Jack L, Leonard Deborah M, Wolfe Scot A, Liu Jilin, Rivera Jaime, Yang Michelle, Leonard Ryan T, Johnson Jacob P S, Kumar Prashant, Liebmann Kate L, Tutto Amanda A, Mou Zhongming, Simin Karl J
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
PLoS One. 2017 Jul 24;12(7):e0181724. doi: 10.1371/journal.pone.0181724. eCollection 2017.
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.
Dickkopf（Dkk）家族的Wnt拮抗剂成员会干扰Wnt诱导的受体组装，并参与轴向模式形成和细胞命运决定。该家族成员之一DKK3不会阻断Wnt受体激活。癌症中Dkk3表达缺失与细胞过度增殖及β-连环蛋白信号失调相关，而DKK3的异位表达会使癌症生长停滞。介导癌细胞中DKK3依赖性阻止β-连环蛋白驱动的细胞增殖的分子事件尚不清楚。在此，我们报告鉴定出一种源自Dkk3基因座的新的细胞内基因产物。这种Dkk3b转录本源自位于Dkk3基因第2内含子中的第二个转录起始位点。它对小鼠早期发育至关重要，并且是β-连环蛋白信号传导和细胞增殖的新识别调节因子。Dkk3b通过在与β-TrCP的核外复合物中捕获细胞质中未磷酸化的β-连环蛋白来中断β-连环蛋白的核转位。这些数据揭示了后生动物中研究最多的信号转导途径之一的新调节因子，并为沉默驱动许多癌症中细胞过度增殖的异常β-连环蛋白信号传导提供了一个全新的、尚未开发的治疗靶点。
