Casein kinase 1 alpha (CK 1α) is a serine/threonine kinase with numerous functions, including regulating the Wnt/β‐catenin and p53 pathways. CK 1α has a well‐established role in inhibiting the p53 tumor suppressor by binding to MDMX and stimulating MDMX ‐p53 interaction. MDMX purified from cells contains near‐stoichiometric amounts of CK 1α, suggesting that MDMX may in turn regulate CK 1α function. We present evidence that MDMX is a potent competitive inhibitor of CK 1α kinase activity (K _i = 8 nM). Depletion of MDMX increases CK 1α activity and β‐catenin S45 phosphorylation, whereas ectopic MDMX expression inhibits CK 1α activity and β‐catenin phosphorylation. The MDMX acidic domain and zinc finger are necessary and sufficient for binding and inhibition of CK 1α. P53 binding to MDMX disrupts an intramolecular auto‐regulatory interaction and enhances its ability to inhibit CK 1α. P53‐null mice expressing the MDMX^{W 200S/W201G} mutant, defective in CK 1α binding, exhibit reduced Wnt/β‐catenin target gene expression and delayed tumor development. Therefore, MDMX is a physiological inhibitor of CK 1α and has a role in modulating cellular response to Wnt signaling. The MDMX ‐CK 1α interaction may account for certain p53‐independent functions of MDMX .

中文翻译：

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MDMX抑制酪蛋白激酶1α活性并刺激Wnt信号传导。

酪蛋白激酶1α（CK1α）是一种丝氨酸/苏氨酸激酶，具有多种功能，包括调节Wnt /β-catenin和p53途径。CK1α通过与MDMX结合并刺激MDMX -p53相互作用而在抑制p53肿瘤抑制因子方面发挥了公认的作用。从细胞中纯化出的MDMX含有接近化学计量的CK1α，这表明MDMX可能进而调节CK1α的功能。我们提供的证据表明MDMX是CK1α激酶活性（K _i = 8 nM）。耗竭MDMX会增加CK1α活性和β-cateninS45磷酸化，而异位MDMX表达会抑制CK1α活性和β-catenin磷酸化。MDMX酸性结构域和锌指对于结合和抑制CK1α是必不可少的。P53与MDMX的结合会破坏分子内的自调节相互作用，并增强其抑制CK1α的能力。表达MDMX ^{W 200S / W201G}突变体，^CK1α结合缺陷的P53空小鼠表现出Wnt /β-catenin靶基因表达降低和肿瘤发展延迟。因此，MDMX是CK1α的生理抑制剂，并在调节细胞对Wnt信号的反应中发挥作用。MDMX -CK1α相互作用可能解释了MDMX的某些独立于p53的功能。