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Tumor-derived CK1α mutations enhance MDMX inhibition of p53

Oncogene volume 39, pages 176–186 (2020)Cite this article

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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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References

  1. Knippschild U, Kruger M, Richter J, Xu P, Garcia-Reyes B, Peifer C, et al. The CK1 family: contribution to cellular stress response and its role in carcinogenesis. Front Oncol. 2014;4:96.

    Article  Google Scholar 

  2. Chen L, Li C, Pan Y, Chen J. Regulation of p53-MDMX interaction by casein kinase 1 alpha. Mol Cell Biol. 2005;25:6509–20.

    Article  CAS  Google Scholar 

  3. Wei X, Wu S, Song T, Chen L, Gao M, Borcherds W, et al. Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding. Proc Natl Acad Sci USA. 2016;113:E2558–63.

    Article  CAS  Google Scholar 

  4. Huart AS, MacLaine NJ, Meek DW, Hupp TR. CK1alpha plays a central role in mediating MDM2 control of p53 and E2F-1 protein stability. J Biol Chem. 2009;284:32384–94.

    Article  CAS  Google Scholar 

  5. Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW. The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev. 1999;13:270–83.

    Article  CAS  Google Scholar 

  6. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149:1192–205.

    Article  CAS  Google Scholar 

  7. Pribluda A, Elyada E, Wiener Z, Hamza H, Goldstein RE, Biton M, et al. A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell. 2013;24:242–56.

    Article  CAS  Google Scholar 

  8. Elyada E, Pribluda A, Goldstein RE, Morgenstern Y, Brachya G, Cojocaru G, et al. CKIalpha ablation highlights a critical role for p53 in invasiveness control. Nature. 2011;470:409–13.

    Article  CAS  Google Scholar 

  9. Schneider RK, Adema V, Heckl D, Jaras M, Mallo M, Lord AM, et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell. 2014;26:509–20.

    Article  CAS  Google Scholar 

  10. Jaras M, Miller PG, Chu LP, Puram RV, Fink EC, Schneider RK, et al. Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. J Exp Med. 2014;211:605–12.

    Article  CAS  Google Scholar 

  11. Sinnberg T, Menzel M, Kaesler S, Biedermann T, Sauer B, Nahnsen S, et al. Suppression of casein kinase 1alpha in melanoma cells induces a switch in beta-catenin signaling to promote metastasis. Cancer Res. 2010;70:6999–7009.

    Article  CAS  Google Scholar 

  12. Smith AE, Kulasekararaj AG, Jiang J, Mian S, Mohamedali A, Gaken J, et al. CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: a retrospective mutational analysis. Lancet Haematol. 2015;2:e212–21.

    Article  Google Scholar 

  13. Heuser M, Meggendorfer M, Cruz MM, Fabisch J, Klesse S, Kohler L, et al. Frequency and prognostic impact of casein kinase 1A1 mutations in MDS patients with deletion of chromosome 5q. Leukemia. 2015;29:1942–5.

    Article  CAS  Google Scholar 

  14. Bello E, Pellagatti A, Shaw J, Mecucci C, Kusec R, Killick S, et al. CSNK1A1 mutations and gene expression analysis in myelodysplastic syndromes with del(5q). Br J Haematol. 2015;171:210–14.

    Article  CAS  Google Scholar 

  15. Komrokji RS, Padron E, Ebert BL, List AF. Deletion 5q MDS: molecular and therapeutic implications. Best Pr Res Clin Haematol. 2013;26:365–75.

    Article  CAS  Google Scholar 

  16. Wang L, Fidler C, Nadig N, Giagounidis A, Della Porta MG, Malcovati L, et al. Genome-wide analysis of copy number changes and loss of heterozygosity in myelodysplastic syndrome with del(5q) using high-density single nucleotide polymorphism arrays. Haematologica. 2008;93:994–1000.

    Article  Google Scholar 

  17. Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, et al. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2010;16:49–58.

    Article  CAS  Google Scholar 

  18. Schneider RK, Schenone M, Ferreira MV, Kramann R, Joyce CE, Hartigan C, et al. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med. 2016;22:288–97.

    Article  CAS  Google Scholar 

  19. Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature. 2008;451:335–9.

    Article  CAS  Google Scholar 

  20. Kulasekararaj AG, Smith AE, Mian SA, Mohamedali AM, Krishnamurthy P, Lea NC, et al. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. Br J Haematol. 2013;160:660–72.

    Article  CAS  Google Scholar 

  21. Kronke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature. 2015;523:183–8.

    Article  CAS  Google Scholar 

  22. Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343:301–5.

    Article  Google Scholar 

  23. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343:305–9.

    Article  CAS  Google Scholar 

  24. Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res. 2017;45:D777–D783.

    Article  CAS  Google Scholar 

  25. Petzold G, Fischer ES, Thoma NH. Structural basis of lenalidomide-induced CK1alpha degradation by the CRL4(CRBN) ubiquitin ligase. Nature. 2016;532:127–30.

    Article  CAS  Google Scholar 

  26. Wu S, Chen L, Becker A, Schonbrunn E, Chen J. Casein kinase 1alpha regulates an MDMX intramolecular interaction to stimulate p53 binding. Mol Cell Biol. 2012;32:4821–32.

    Article  CAS  Google Scholar 

  27. Drexler HG, Dirks WG, Macleod RA. Many are called MDS cell lines: one is chosen. Leuk Res. 2009;33:1011–6.

    Article  CAS  Google Scholar 

  28. Tsujioka T, Yokoi A, Uesugi M, Kishimoto M, Tochigi A, Suemori S, et al. Effects of DNA methyltransferase inhibitors (DNMTIs) on MDS-derived cell lines. Exp Hematol. 2013;41:189–97.

    Article  CAS  Google Scholar 

  29. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science. 1997;275:1784–7.

    Article  CAS  Google Scholar 

  30. Sobrado P, Jedlicki A, Bustos VH, Allende CC, Allende JE. Basic region of residues 228-231 of protein kinase CK1alpha is involved in its interaction with axin: binding to axin does not affect the kinase activity. J Cell Biochem. 2005;94:217–24.

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Molecular Oncology Department, Moffitt Cancer Center, 12902 Magnolia Drive, 33612, Tampa, FL, USA

    Xia Liu, Qingling Huang, Lihong Chen & Jiandong Chen

  2. Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, 300060, Tianjin, China

    Xia Liu & Huilai Zhang

  3. Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA

    Ernst Schonbrunn

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  1. Xia Liu
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Contributions

Experimental work: XL, QH, LC. Experimental design: XL, QH, LC, HZ, JC. Writing of manuscript: ES, JC. Study conception: JC

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Correspondence to Jiandong Chen.

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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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