Cables1 controls p21/Cip1 protein stability by antagonizing proteasome subunit alpha type 3

• Published in: Oncogene Vol. 34; no. 19; pp. 2538 - 2545
• Main Authors: Shi, Z, Li, Z, Li, Z J, Cheng, K, Du, Y, Fu, H, Khuri, F R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.05.2015; Nature Publishing Group
• Subjects: 631/80/641; 82/1; 82/80; 96/106; 96/31; 96/95; Analysis; Apoptosis; Apoptosis - genetics; Cancer therapies; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell activation; Cell Biology; Cell cycle; Cell death; Cell differentiation; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-dependent kinase 5; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-dependent kinases; Cyclins - biosynthesis; Cyclins - genetics; Cyclins - metabolism; Enzyme inhibitors; Genetic transcription; GTP-binding protein; Health aspects; HEK293 Cells; Human Genetics; Humans; Internal Medicine; Kinases; Localization; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Oncology; original-article; Phosphoproteins - biosynthesis; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Binding; Proteins; Proteolysis; RNA Interference; RNA, Small Interfering; Stability; Therapeutic applications; Tumor cell lines; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.171

The cyclin-dependent kinase (CDK) inhibitor 1A, p21/Cip1, is a vital cell cycle regulator, dysregulation of which has been associated with a large number of human malignancies. One critical mechanism that controls p21 function is through its degradation, which allows the activation of its associated cell cycle-promoting kinases, CDK2 and CDK4. Thus delineating how p21 is stabilized and degraded will enhance our understanding of cell growth control and offer a basis for potential therapeutic interventions. Here we report a novel regulatory mechanism that controls the dynamic status of p21 through its interaction with C dk5 and Abl e nzyme s ubstrate 1 (Cables1). Cables1 has a proposed role as a tumor suppressor. We found that upregulation of Cables1 protein was correlated with increased half-life of p21 protein, which was attributed to Cables1/p21 complex formation and supported by their co-localization in the nucleus. Mechanistically, Cables1 interferes with the proteasome (Prosome, Macropain) subunit alpha type 3 (PSMA3) binding to p21 and protects p21 from PSMA3-mediated proteasomal degradation. Moreover, silencing of p21 partially reverses the ability of Cables1 to induce cell death and inhibit cell proliferation. In further support of a potential pathophysiological role of Cables1, the expression level of Cables1 is tightly associated with p21 in both cancer cell lines and human lung cancer patient tumor samples. Together, these results suggest Cables1 as a novel p21 regulator through maintaining p21 stability and support the model that the tumor-suppressive function of Cables1 occurs at least in part through enhancing the tumor-suppressive activity of p21.