The Tumor Suppressor Cdkn3 Is Required for Maintaining the Proper Number of Centrosomes by Regulating the Centrosomal Stability of Mps1

Abstract

Supernumerary centrosomes promote the assembly of abnormal spindles in many human cancers. The observation that modest changes in the centrosomal levels of Mps1 kinase can cause centrosome overduplication in human cells suggests the existence of a regulatory system that may tightly control its centrosomal stability. Here, we show that Cdkn3, a Cdk-associated phosphatase, prevents Mps1-mediated centrosome overduplication. We identify Cdkn3 as a direct binding partner of Mps1. The interaction between Mps1 and Cdkn3 is required for Mps1 to recruit Cdkn3 to centrosomes. Subsequently, Mps1-bound Cdkn3 forms a regulatory system that controls the centrosomal levels of Mps1 through proteasome-mediated degradation and thereby prevents Mps1-mediated centrosome overduplication. Conversely, knockdown of Cdkn3 stabilizes Mps1 at centrosomes, which promotes centrosome overduplication. We suggest that Mps1 and Cdkn3 form a self-regulated feedback loop at centrosomes to tightly control the centrosomal levels of Mps1, which prevents centrosome overduplication in human cells.

DNA replication licensing factor Cdc6 and Plk4 kinase antagonistically regulate centrosome duplication via Sas-6

“…PIPKIγ restrains centriole duplication by interacting with Plk4 and negatively regulating its kinase activity49. Cdkn3 prevents Mps1 kinase-mediated centrosome over-duplication by regulating Mps1 protein stability50. In addition, KLF14 represses centrosome amplification by transcriptionally inhibiting the Plk4 protein level51.…”

Modular elements of the TPR domain in the Mps1 N terminus differentially target Mps1 to the centrosome and kinetochore

“…Because Mps1 centrosomal levels are tightly regulated by the proteasome-dependent degradation of Mps1 at centrosomes (18,20,27), we tested whether the reduced centrosomal accumulation of GFP-Mps1…”

mRNA expression and DNA methylation analysis of the inhibitory mechanism of H₂O₂ on the proliferation of A549 cells

“…Another study obtained similar results, revealing that increased expression levels of HIST1H2BM were associated with a poor survival in patients with LUAD and may act as a potential biomarker of drug synergy for the future clinical trials (21). Although in the previous study CDK3 has been reported as a tumour suppressor by maintaining the proper number of centrosomes (22), CDKN3 has also been demonstrated to be a potential poor prognostic marker in LUAD through the systematic analysis of datasets in Lung Cancer Explorer (23). Another report further proved that CDKN3 upregulation, which is mainly caused by the increase of mitotic activity, may be associated with poor survival in patients with LUAD, arguing against CDKN3 as a tumour suppressor (24).…”