|Title:||14-3-3σ regulates β-catenin-mediated mouse embryonic stem cell proliferation by sequestering GSK-3β.||Authors:||Chang, Tzu-Ching
Yen, B. Linju
Wu, Kenneth K.
|Issue Date:||2012||Source:||PLoS One||Journal Volume:||7||Journal Issue:||6||Start page/Pages:||-||Abstract:||
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.
|Appears in Collections:||醫學系|
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