Centre Hospitalier Université Laval Research Center, Québec, QC, Canada G1V 4G2 and Departments of Psychiatry and Neurosciences and Pediatrics, Université Laval, Québec, QC, Canada G1V 0A6.
Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2152-7. doi: 10.1073/pnas.1314226111. Epub 2014 Jan 27.
Fanconi anemia (FA) is an inherited bone marrow failure syndrome associated with a progressive decline in hematopoietic stem cells, developmental defects, and predisposition to cancer. These various phenotypic features imply a role of FA proteins in molecular events regulating cellular homeostasis. Interestingly, we previously found that the Fanconi C protein (FANCC) interacts with the C-terminal-binding protein-1 (CtBP1) involved in transcriptional regulation. Here we report that FANCC with CtBP1 forms a complex with β-catenin, and that β-catenin activation through glycogen synthase kinase 3β inhibition leads to FANCC nuclear accumulation and FA pathway activation, as measured by the Fanconi D2 protein (FANCD2) monoubiquitination. β-catenin and FANCC nuclear entry is defective in FA mutant cells and in cells depleted of the Fanconi A protein or FANCD2, suggesting that integrity of the FA pathway is required for FANCC nuclear activity. We also report that FANCC with CtBP1 acts as a negative regulator of Dickkopf-1 (DKK1) expression, and that a FA disease-causing mutation in FANCC abrogates this function. Our findings reveal that a defective FA pathway leads to up-regulation of DKK1, a molecule involved in hematopoietic malignancies.
范可尼贫血症（FA）是一种遗传性骨髓衰竭综合征，与造血干细胞的逐渐减少、发育缺陷和癌症易感性有关。这些不同的表型特征表明 FA 蛋白在调节细胞内稳态的分子事件中起作用。有趣的是，我们之前发现 Fanconi C 蛋白（FANCC）与参与转录调控的 C 端结合蛋白 1（CtBP1）相互作用。在这里，我们报告 FANCC 与 CtBP1 形成与β-连环蛋白的复合物，并且通过抑制糖原合酶激酶 3β 导致β-连环蛋白激活，从而导致 FANCC 核积累和 FA 途径激活，如通过 Fanconi D2 蛋白（FANCD2）单泛素化来测量。FA 突变细胞和耗尽 Fanconi A 蛋白或 FANCD2 的细胞中β-连环蛋白和 FANCC 核进入均存在缺陷，这表明 FA 途径的完整性是 FANCC 核活性所必需的。我们还报告 FANCC 与 CtBP1 作为 Dickkopf-1（DKK1）表达的负调节剂，并且 FANCC 中的 FA 疾病相关突变会破坏这种功能。我们的发现揭示了有缺陷的 FA 途径导致造血恶性肿瘤相关分子 DKK1 的上调。
