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COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3σ

Oncogene volume 30, pages 4791–4801 (2011)Cite this article

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Abstract

14-3-3σ, a gene upregulated by p53 in response to DNA damage, exists as part of a positive-feedback loop, which activates p53 and is a human cancer epithelial marker downregulated in various cancer types. 14-3-3σ levels are critical for maintaining p53 activity in response to DNA damage and regulating signal mediators such as Akt. In this study, we identify mammalian constitutive photomorphogenic 1 (COP1) as a novel E3 ubiquitin ligase for targeting 14-3-3σ through proteasomal degradation. We show for the first time that COP9 signalosome subunit 6 (CSN6) associates with COP1 and is involved in 14-3-3σ ubiquitin-mediated degradation. Mechanistic studies show that CSN6 expression leads to stabilization of COP1 through reducing COP1 self-ubiquitination and decelerating COP1's turnover rate. We also show that CSN6-mediated 14-3-3σ ubiquitination is compromised when COP1 is knocked down. Thus, CSN6 mediates 14-3-3σ ubiquitination through enhancing COP1 stability. Subsequently, we show that CSN6 causes 14-3-3σ downregulation, thereby activating Akt and promoting cell survival. Also, CSN6 overexpression leads to increased cell growth, transformation and promotes tumorigenicity. Significantly, 14-3-3σ expression can correct the abnormalities mediated by CSN6 expression. These data suggest that the CSN6-COP1 axis is involved in 14-3-3σ degradation, and that deregulation of this axis will promote cell growth and tumorigenicity.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH) (R01CA089266), Directed Medical Research Programs (DOD SIDA BC062166 to SJY and MHL) and Susan G Komen Breast Cancer Foundation (KG081048). This research was supported in part, by a cancer prevention fellowship for GVT (R25T CA57730). The University of Texas MD Anderson Cancer Center is supported by NIH core Grant CA16672.

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  1. C Gully and C-H Su: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    H H Choi, C Gully, C-H Su, G Velazquez-Torres, P-C Chou, C Tseng, R Zhao, L Phan, T Shaiken, J Chen & M-H Lee

  2. Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    H H Choi, G Velazquez-Torres, P-C Chou, C Tseng & M-H Lee

  3. Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    C Gully, C-H Su & M-H Lee

  4. Department of General Internal Medicine, Ambulatory Treatment, and Emergency Care, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    S C Yeung

  5. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    S C Yeung

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  1. H H Choi
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Correspondence to S C Yeung or M-H Lee.

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Choi, H., Gully, C., Su, CH. et al. COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3σ. Oncogene 30, 4791–4801 (2011). https://doi.org/10.1038/onc.2011.192

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