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- Title
Negative cell cycle regulator 14-3-3σ stabilizes p27 Kip1 by inhibiting the activity of PKB/Akt.
- Authors
Yang, H.; Zhang, Y.; Zhao, R.; Wen, Y.-Y.; Fournier, K.; Wu, H.-B.; Yang, H.-Y.; Diaz, J.; Laronga, C.; Lee, M.-H.
- 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.Oncogene (2006) 25, 4585–4594. doi:10.1038/sj.onc.1209481; published online 13 March 2006
- Subjects
CELL cycle; GROWTH factors; PROTEIN kinases; ONCOGENES; BREAST cancer; CYTOPLASM; GENE therapy; ANTINEOPLASTIC agents
- Publication
Oncogene, 2006, Vol 25, Issue 33, p4585
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1209481