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Negative cell cycle regulator 14-3-3σ stabilizes p27 Kip1 by inhibiting the activity of PKB/Akt

Oncogene volume 25, pages 4585–4594 (2006)Cite this article

Abstract

The 14-3-3σ (sigma) protein is a human cancer marker downregulated in various tumors, but its function has not been fully established. 14-3-3σ is a negative regulator of cell cycle when overexpressed, but it is not clear whether 14-3-3σ regulates cyclin-dependent kinase inhibitor p27Kip1 to negatively affect cell cycle progression. Protein kinase B/Akt is a crucial regulator of oncogenic signal and can phosphorylate p27Kip1 to enhance p27Kip1degradation, thereby promoting cell growth. Here, we show that 14-3-3σ-mediated cell cycle arrest concurred with p27Kip1 upregulation and Akt inactivation. We show that 14-3-3σ blocks Akt-mediated acceleration of p27Kip1 turnover rate. 14-3-3σ inhibits Akt-mediated p27Kip1 phosphorylation that targets p27Kip1 for nuclear export and degradation. 14-3-3σ inhibits cell survival and tumorigenicity of Akt-activating breast cancer cell. Low expression of 14-3-3σ in human primary breast cancers correlates with cytoplasmic location of p27Kip1. These data provide an insight into 14-3-3σ activity and rational cancer gene therapy by identifying 14-3-3σ as a positive regulator of p27 and as a potential anticancer agent.

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Acknowledgements

We thank Drs Vogelstein and Hung for valuable reagents, and Drs Lozano, Legerski and Behringer for critical reading and comments. This work was supported by the NIHRO1CA (089266) and Cancer Center Core Grant (CA16672). M-H Lee is a recipient of the Flemin and Davenport research award and the Susan G Koman Breast Cancer Foundation research award.

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Author notes

  1. H Yang

    Present address: Department of Pathophysiology, Zhongshan University, China

  2. Y Zhang, R Zhao and Y-Y Wen: These authors contributed equally to this work.

Authors and Affiliations

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

    H Yang, Y Zhang, R Zhao, Y-Y Wen, H-B Wu, H-Y Yang & M-H Lee

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

    R Zhao, Y-Y Wen & M-H Lee

  3. Department of Surgery, Eastern Virginia Medical School, Norfolk, VA, USA

    K Fournier, J Diaz & C Laronga

  4. Breast Cancer Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M-H Lee

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

    M-H Lee

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Yang, H., Zhang, Y., Zhao, R. et al. Negative cell cycle regulator 14-3-3σ stabilizes p27 Kip1 by inhibiting the activity of PKB/Akt. Oncogene 25, 4585–4594 (2006). https://doi.org/10.1038/sj.onc.1209481

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