Abstract
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.
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Acknowledgements
We would like to thank the Moffitt Flow Cytometry Core. This work was supported in part by grants from the National Institutes of Health (CA141244, CA186917) (JC), and by the NCI Cancer Center Support Grant P30-CA076292. XL was partly supported by Tianjin Medical University Cancer Institute and Hospital.
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Experimental work: XL, QH, LC. Experimental design: XL, QH, LC, HZ, JC. Writing of manuscript: ES, JC. Study conception: JC
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Liu, X., Huang, Q., Chen, L. et al. Tumor-derived CK1α mutations enhance MDMX inhibition of p53. Oncogene 39, 176–186 (2020). https://doi.org/10.1038/s41388-019-0979-z
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DOI: https://doi.org/10.1038/s41388-019-0979-z