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

H. Yang; Y. Zhang; R. Zhao; Y. Y. Wen; K. Fournier; H. B. Wu; H. Y. Yang; J. Diaz; C. Laronga; Mong-Hong Lee

doi:10.1038/sj.onc.1209481

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

H. Yang, Y. Zhang, R. Zhao, Y. Y. Wen, K. Fournier, H. B. Wu, H. Y. Yang, J. Diaz, C. Laronga, Mong-Hong Lee

Molecular & Cellular Oncology

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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 p27 ^Kip1 to negatively affect cell cycle progression. Protein kinase B/Akt is a crucial regulator of oncogenic signal and can phosphorylate p27 ^Kip1 to enhance p27^Kip1degradation, thereby promoting cell growth. Here, we show that 14-3-3σ-mediated cell cycle arrest concurred with p27^Kip1 upregulation and Akt inactivation. We show that 14-3-3σ blocks Akt-mediated acceleration of p27^Kip1 turnover rate. 14-3-3σ inhibits Akt-mediated p27^Kip1 phosphorylation that targets p27^Kip1 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 p27^Kip1. 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.

Original language	English (US)
Pages (from-to)	4585-4594
Number of pages	10
Journal	Oncogene
Volume	25
Issue number	33
DOIs	https://doi.org/10.1038/sj.onc.1209481
State	Published - Aug 3 2006

Keywords

14-3-3
Akt
Tumor suppression
p27

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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10.1038/sj.onc.1209481

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

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 p27 Kip1 to negatively affect cell cycle progression. Protein kinase B/Akt is a crucial regulator of oncogenic signal and can phosphorylate p27 Kip1 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.",

keywords = "14-3-3, Akt, Tumor suppression, p27",

author = "H. Yang and Y. Zhang and R. Zhao and Wen, {Y. Y.} and K. Fournier and Wu, {H. B.} and Yang, {H. Y.} and J. Diaz and C. Laronga and Mong-Hong Lee",

note = "Funding Information: 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.",

year = "2006",

month = aug,

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doi = "10.1038/sj.onc.1209481",

language = "English (US)",

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AU - Yang, H.

AU - Zhang, Y.

AU - Zhao, R.

AU - Wen, Y. Y.

AU - Fournier, K.

AU - Wu, H. B.

AU - Yang, H. Y.

AU - Diaz, J.

AU - Laronga, C.

AU - Lee, Mong-Hong

N1 - Funding Information: 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.

PY - 2006/8/3

Y1 - 2006/8/3

N2 - 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 p27 Kip1 to negatively affect cell cycle progression. Protein kinase B/Akt is a crucial regulator of oncogenic signal and can phosphorylate p27 Kip1 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.

AB - 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 p27 Kip1 to negatively affect cell cycle progression. Protein kinase B/Akt is a crucial regulator of oncogenic signal and can phosphorylate p27 Kip1 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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JO - Oncogene

JF - Oncogene

IS - 33

ER -

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

Abstract

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