14-3-3σ Regulates β-Catenin-Mediated Mouse Embryonic Stem Cell Proliferation by Sequestering GSK-3β

被引:24
作者
Chang, Tzu-Ching [1 ]
Liu, Chia-Chia [1 ,2 ]
Hsing, En-Wei [1 ]
Liang, Shu-Man [1 ]
Chi, Ya-Hui [1 ]
Sung, Li-Ying [2 ]
Lin, Shau-Ping [2 ]
Shen, Tang-Long [3 ]
Ko, Bor-Sheng [1 ,4 ]
Yen, B. Linju [1 ]
Yet, Shaw-Fang [1 ]
Wu, Kenneth K. [1 ]
Liou, Jun-Yang [1 ]
机构
[1] Natl Hlth Res Inst, Inst Cellular & Syst Med, Zhunan, Taiwan
[2] Natl Taiwan Univ, Inst Biotechnol, Taipei 10764, Taiwan
[3] Natl Taiwan Univ, Dept Plant Pathol & Microbiol, Taipei 10764, Taiwan
[4] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan
关键词
EFFICIENT TRANSFECTION METHOD; NEURAL DIFFERENTIATION; STRUCTURAL BASIS; RETINOIC ACID; ACTIVATION; PHOSPHORYLATION; KINASE; CANCER; PROTEINS; PLURIPOTENCY;
D O I
10.1371/journal.pone.0040193
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
Background: Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear. Methodology and Principal Findings: In this study, we show that all seven 14-3-3 isoforms were detected in mouse embryonic stem cells. Retinoid acid suppressed selectively the expression of 14-3-3 sigma isoform. Knockdown of 14-3-3 sigma with siRNA reduced embryonic stem cell proliferation, while only 14-3-3 sigma transfection increased cell growth and partially rescued retinoid acid-induced growth arrest. Since the growth-enhancing action of 14-3-3s was abrogated by beta-catenin knockdown, we investigated the influence of 14-3-3 sigma overexpression on beta-catenin/GSK-3 beta. 14-3-3 sigma bound GSK-3 beta and increased GSK-3 beta phosphorylation in a PI-3K/Akt-dependent manner. It disrupted beta-catenin binding by the multiprotein destruction complex. 14-3-3 sigma overexpression attenuated beta-catenin phosphorylation and rescued the decline of beta-catenin induced by retinoid acid. Furthermore, 14-3-3 sigma enhanced Wnt3a-induced beta-catenin level and GSK-3 beta phosphorylation. DKK, an inhibitor of Wnt signaling, abolished Wnt3a-induced effect but did not interfere GSK-3b/14-3-3 sigma binding. Significance: Our findings show for the first time that 14-3-3 sigma plays an important role in regulating mouse embryonic stem cell proliferation by binding and sequestering phosphorylated GSK-3 beta and enhancing Wnt-signaled GSK-3 beta inactivation. 14-3-3 sigma is a novel target for embryonic stem cell expansion.
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页数:11
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