Tumor-derived CK1? mutations enhance MDMX inhibition of p53.

ABSTRACT: Somatic missense mutations of the CSNK1A1 gene encoding casein kinase 1 alpha (CK1?) occur in a subset of myelodysplastic syndrome (MDS) with del(5q) karyotype. The chromosomal deletion causes CSNK1A1 haplo-insufficiency. CK1? mutations have also been observed in a variety of solid and hematopoietic tumors at low frequency. The functional consequence of CK1? mutation remains unknown. Here we show that tumor-associated CK1? 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 ?-catenin, resulting in enhanced Wnt signaling. The results suggest that the CK1? 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.

SUBMITTER: Liu X 

PROVIDER: S-EPMC7739390 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature