Abstract
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.
Highlights
The Cks proteins are small phospho-adapters required for correct CDK substrate recognition, and more precisely, for the specification of multisite phosphorylation [1,2]
The first evidence that the Mll1 protein may be under the control of the Cks1/Cks2 axis is based on Mll1 biphasic, cell-cycle dependent regulation by the SCFSkp2 and APCCdc20 ubiquitin E3 ligase complexes, both of which require Cks for degradation of a portion of their known targets
Previous studies, describing the requirement of Cks1 [8,47] and Cks2 [8,13] in cell cycle dynamics, have postulated that targets of the Cks1/Cks2 axis may extend beyond the specific subset of Cyclins and CKIs [5,7,10,13,62]
Summary
The Cks proteins are small phospho-adapters required for correct CDK substrate recognition (but not kinase activity), and more precisely, for the specification of multisite phosphorylation [1,2]. It has been shown that Cks and Cks associate with two ubiquitin E3 ligase complexes, SCFSkp and APCCdc, thereby regulating degradation of Cyclin A and the CDK inhibitor p27 [7,8]. Cks brings p27 to Skp, facilitating p27 ubiquitination and degradation, while Cks protects p27 from Skp interactions and stabilises p27 [7,8,12]. Whereas both Cks1−/− and Cks2−/− mice are viable [7,13], the Cks and Cks double knockout is embryonic lethal after the morula stage, indicating that Cks and Cks are essential for embryonic development [5]. CKS1B and CKS2 are frequently overexpressed in various cancers [16,17,18,19], including multiple myeloma [20,21] and breast cancer [6,22,23], correlating with increased proliferation and poor prognosis
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