βTrCP controls the lysosome-mediated degradation of CDK1, whose accumulation correlates with tumor malignancy

• Published in: Oncotarget 2014-09, Vol.5 (17), p.7563-7574
• Main Authors: Herrero-Ruiz, Joaquín, Mora-Santos, Mar, Giráldez, Servando, Sáez, Carmen, Japón, Miguel A, Tortolero, Maria, Romero, Francisco
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; CDC2 Protein Kinase - metabolism; Cell Line; Humans; Immunoprecipitation; Lysosomes - metabolism; Neoplasm Invasiveness - pathology; Neoplasms - metabolism; Neoplasms - pathology; Research Paper; RNA, Small Interfering; SKP Cullin F-Box Protein Ligases - metabolism; Tandem Mass Spectrometry; Tissue Array Analysis; Transfection
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.2274

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.