Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Tumor-derived CK1α mutations enhance MDMX inhibition of p53.
Oncogene ( IF 6.9 ) Pub Date : 2019-08-28 , DOI: 10.1038/s41388-019-0979-z
Xia Liu 1, 2 , Qingling Huang 1 , Lihong Chen 1 , Huilai Zhang 2 , Ernst Schonbrunn 3 , Jiandong Chen 1
Oncogene ( IF 6.9 ) Pub Date : 2019-08-28 , DOI: 10.1038/s41388-019-0979-z
Xia Liu 1, 2 , Qingling Huang 1 , Lihong Chen 1 , Huilai Zhang 2 , Ernst Schonbrunn 3 , Jiandong Chen 1
Affiliation
|
Somatic missense mutations of the CSNK1A1 gene encoding casein kinase 1 alpha (CK1α) occur in a subset of myelodysplastic syndrome (MDS) with del(5q) karyotype. The chromosomal deletion causes CSNK1A1 haplo-insufficiency. CK1α mutations have also been observed in a variety of solid and hematopoietic tumors at low frequency. The functional consequence of CK1α mutation remains unknown. Here we show that tumor-associated CK1α mutations exclusively localize to the substrate-binding cleft. Functional analysis of recurrent mutants E98K and D140A revealed enhanced binding to the p53 inhibitor MDMX, increased ability to stimulate MDMX-p53 binding, and increased suppression of p21 expression. Furthermore, E98K and D140A mutants have reduced ability to promote phosphorylation of β-catenin, resulting in enhanced Wnt signaling. The results suggest that the CK1α mutations observed in tumors cause gain-of-function in cooperating with MDMX and inhibiting p53, and partial loss-of-function in suppressing Wnt signaling. These functional changes may promote expansion of abnormal myeloid progenitors in del(5q) MDS, and in rare cases drive the progression of other tumors.
中文翻译：
肿瘤来源的CK1α突变可增强MDMX对p53的抑制作用。
编码酪蛋白激酶1α（CK1α）的CSNK1A1基因的体细胞错义突变发生在具有del（5q）核型的骨髓增生异常综合症（MDS）的子集中。染色体缺失导致CSNK1A1单倍功能不足。CK1α突变也已在各种实体和造血肿瘤中低频率观察到。CK1α突变的功能后果仍然未知。在这里，我们显示肿瘤相关的CK1α突变专门定位于与底物结合的裂口。复发突变体E98K和D140A的功能分析表明，与p53抑制剂MDMX的结合增强，刺激MDMX-p53结合的能力增强，对p21表达的抑制作用增强。此外，E98K和D140A突变体促进β-catenin磷酸化的能力降低，导致增强的Wnt信号传导。结果表明，在肿瘤中观察到的CK1α突变导致与MDMX协同作用并抑制p53的功能获得，并在抑制Wnt信号转导中导致部分功能丧失。这些功能更改可能会促进del（5q）MDS中异常髓样祖细胞的扩增，在极少数情况下会驱动其他肿瘤的进展。
更新日期：2019-08-28
中文翻译：
肿瘤来源的CK1α突变可增强MDMX对p53的抑制作用。
编码酪蛋白激酶1α（CK1α）的CSNK1A1基因的体细胞错义突变发生在具有del（5q）核型的骨髓增生异常综合症（MDS）的子集中。染色体缺失导致CSNK1A1单倍功能不足。CK1α突变也已在各种实体和造血肿瘤中低频率观察到。CK1α突变的功能后果仍然未知。在这里，我们显示肿瘤相关的CK1α突变专门定位于与底物结合的裂口。复发突变体E98K和D140A的功能分析表明，与p53抑制剂MDMX的结合增强，刺激MDMX-p53结合的能力增强，对p21表达的抑制作用增强。此外，E98K和D140A突变体促进β-catenin磷酸化的能力降低，导致增强的Wnt信号传导。结果表明，在肿瘤中观察到的CK1α突变导致与MDMX协同作用并抑制p53的功能获得，并在抑制Wnt信号转导中导致部分功能丧失。这些功能更改可能会促进del（5q）MDS中异常髓样祖细胞的扩增，在极少数情况下会驱动其他肿瘤的进展。
京公网安备 11010802027423号