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

Oncogene volume 34, pages 2538–2545 (2015)Cite this article

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Abstract

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 Cdk5 and Abl enzyme substrate 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.

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Acknowledgements

We thank the past and present members of the Fu/Khuri laboratory for many stimulating discussions. We also thank Dr Zukerberg LR and Dr Rueda BR (Massachusetts General Hospital) for sharing reagents. This work was supported by the National Institutes of Health Grant P01 CA116676 (to FRK and HF), Georgia Cancer Coalition (to HF and FRK), the Chinese National Natural Science Foundation No. 31271444 and No. 81201726 (to ZS), the Foundation for Research Cultivation and Innovation of Jinan University No. 21612407 (to ZS), the Science and Technology Program of Guangzhou No. 14200010 ( to ZS) and the Specialized Research Fund for the Doctoral Program of Higher Education No. 20124401120007 (to ZS).

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Authors and Affiliations

  1. Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China

    Z Shi

  2. Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA

    Z Shi, Z Li, Z J Li, K Cheng, Y Du & H Fu

  3. Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China

    Z J Li

  4. Chemical Biology Center, Lishui Institute of Agricultural Sciences, Lishui, China

    K Cheng

  5. Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA, USA

    Y Du, H Fu & F R Khuri

  6. Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA

    H Fu & F R Khuri

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  1. Z Shi
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Correspondence to H Fu or F R Khuri.

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Shi, Z., Li, Z., Li, Z. et al. Cables1 controls p21/Cip1 protein stability by antagonizing proteasome subunit alpha type 3. Oncogene 34, 2538–2545 (2015). https://doi.org/10.1038/onc.2014.171

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