Abstract
In mammals, cell cycle progression is controlled by cyclin-dependent kinases, among which CDK1 plays important roles in the regulation of the G2/M transition, G1 progression and G1/S transition. CDK1 is highly regulated by its association to cyclins, phosphorylation and dephosphorylation, changes in subcellular localization, and by direct binding of CDK inhibitor proteins. CDK1 steady-state protein levels are held constant throughout the cell cycle by a coordinated regulation of protein synthesis and degradation. We show that CDK1 is ubiquitinated by the E3 ubiquitin ligase SCFβTrCP and degraded by the lysosome. Furthermore, we found that DNA damage not only triggers the stabilization of inhibitory phosphorylation sites on CDK1 and repression of CDK1 gene expression, but also regulates βTrCP-induced CDK1 degradation in a cell type-dependent manner. Specifically, treatment with the chemotherapeutic agent doxorubicin in certain cell lines provokes CDK1 degradation and induces apoptosis, whereas in others it inhibits destruction of the protein. These observations raise the possibility that different tumor types, depending on their pathogenic spectrum mutations, may display different sensitivity to βTrCP-induced CDK1 degradation after DNA damage. Finally, we found that CDK1 accumulation in patients' tumors shows a negative correlation with βTrCP and a positive correlation with the degree of tumor malignancy.
Highlights
Cell cycle progression is regulated by a series of cyclin-dependent kinases (CDKs), among which CDK1 has been primarily implicated in G2/M transition, mainly in association with cyclin B
It has been shown that CDK1 transcription/ translation oscillates in a cell cycle-specific manner [11]
CDK1 levels are constant during the normal cell cycle
Summary
Cell cycle progression is regulated by a series of cyclin-dependent kinases (CDKs), among which CDK1 has been primarily implicated in G2/M transition, mainly in association with cyclin B (see [1] for review). CDK1 is able to regulate G1 progress and G1/S transition [2, 3]. Given its essential role in the cell cycle, CDK1 is highly regulated. CDK1 requires the association of one cyclin to recognize and phosphorylate its substrates [4]. Phosphorylation at Thr161 increases the complex activity, whereas phosphorylation at Thr and Tyr leads to inhibition of CDK1. CDK1 protein levels are held at a constant steady-state level throughout the cell cycle, which is maintained by a coordinated regulation of protein synthesis and degradation [11]. It has been shown that CDK1 is downregulated under genotoxic stresses, that double-stranded RNAactivated protein kinase (PKR) is involved in the process and that PKR-mediated Tyr4-phosphorylation facilitates www.impactjournals.com/oncotarget. CDK1 ubiquitination and proteosomal degradation [12]. We found that CDK1 accumulation in patients’ tumors shows a negative correlation with βTrCP levels and a positive correlation with the degree of tumor malignancy
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