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The Cdc28 protein kinase subunits, Cks1 and Cks2, play dual roles in Cdk-substrate specificity and Cdk-independent protein degradation, in concert with the E3 ubiquitin ligase complexes SCFSkp2 and APCCdc20. Notable targets controlled by Cks include p27 and Cyclin A. Here, we demonstrate that Cks1 and Cks2 proteins interact with both the MllN and MllC subunits of Mll1 (Mixed-lineage leukaemia 1), and together, the Cks proteins define Mll1 levels throughout the cell cycle. Overexpression of CKS1B and CKS2 is observed in multiple human cancers, including various MLL-rearranged (MLLr) AML subtypes. To explore the importance of MLL-Fusion Protein regulation by CKS1/2, we used small molecule inhibitors (MLN4924 and C1) to modulate their protein degradation functions. These inhibitors specifically reduced the proliferation of MLLr cell lines compared to primary controls. Altogether, this study uncovers a novel regulatory pathway for MLL1, which may open a new therapeutic approach to MLLr leukaemia.

Original publication

DOI

10.1016/j.bbamcr.2017.09.009

Type

Journal article

Journal

Biochim Biophys Acta Mol Cell Res

Publication Date

01/2018

Volume

1865

Pages

105 - 116

Keywords

CKS1B, CKS2, MLL-fusion proteins, MLL1, SKP2/CKS1 inhibitor, Wnt, Animals, CDC2-CDC28 Kinases, CDC28 Protein Kinase, S cerevisiae, Carrier Proteins, Cell Cycle Proteins, Cell Survival, Cells, Cultured, Embryo, Mammalian, Gene Expression Regulation, Leukemic, Gene Rearrangement, Histone-Lysine N-Methyltransferase, Humans, Leukemia, Mice, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Signal Transduction