Fibroblast growth factor receptor-mediated activation of AKT-β-catenin-CBP pathway regulates survival and proliferation of murine hepatoblasts and hepatic tumor initiating stem cells.
Fibroblast growth factor receptor-mediated activation of AKT-β-catenin-CBP pathway regulates survival and proliferation of murine hepatoblasts and hepatic tumor initiating stem cells.
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DOI：
10.1371/journal.pone.0050401
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang KS
中科院分区：
文献类型：
--
作者：
Mavila N;James D;Utley S;Cu N;Coblens O;Mak K;Rountree CB;Kahn M;Wang KS
成纤维细胞生长因子（FGF）-10通过Wnt-β-catenin依赖性途径在肝发生的早期促进小鼠成肝细胞的增殖和存活。为了确定这种情况发生的机制，我们在重组（r）FGF 10或rFGF 7条件培养基中扩增了来自胚胎（E）12.5天胎肝的富含祖细胞标志物CD 133和CD 49 f的成肝细胞和来自Mat 1a −/−肝的已建立的肿瘤起始干细胞系的原代培养物。FGF受体（R）活化导致MAPK、PI 3 K-AKT和β-连环蛋白途径的下游活化以及细胞增殖。此外，在培养的原代肝母细胞、Mat 1a −/−细胞以及离体胚胎肝外植体中，丝氨酸-552磷酸化的核β-连环蛋白水平增加，表明FGFR激活下游的β-连环蛋白的AKT依赖性激活;相反，添加AKT抑制剂Ly 294002完全消除了β-连环蛋白的激活。FGFR激活诱导的细胞增殖和存活也被化合物ICG-001抑制，ICG-001是成肝细胞中β-连环蛋白-CREB结合蛋白（CBP）的小分子抑制剂，进一步表明β-连环蛋白活性的CBP依赖性调节机制。 结论：FGF信号传导部分地通过AKT介导的β-连环蛋白的活化和与转录共激活因子CBP的下游相互作用来调节胚胎和转化祖细胞的增殖和存活。
Fibroblast Growth Factor (FGF)-10 promotes the proliferation and survival of murine hepatoblasts during early stages of hepatogenesis through a Wnt-β-catenin dependent pathway. To determine the mechanism by which this occurs, we expanded primary culture of hepatoblasts enriched for progenitor markers CD133 and CD49f from embryonic day (E) 12.5 fetal liver and an established tumor initiating stem cell line from Mat1a−/− livers in media conditioned with recombinant (r) FGF10 or rFGF7. FGF Receptor (R) activation resulted in the downstream activation of MAPK, PI3K-AKT, and β-catenin pathways, as well as cellular proliferation. Additionally, increased levels of nuclear β-catenin phosphorylated at Serine-552 in cultured primary hepatoblasts, Mat1a−/− cells, and also in ex vivo embryonic liver explants indicate AKT-dependent activation of β-catenin downstream of FGFR activation; conversely, the addition of AKT inhibitor Ly294002 completely abrogated β-catenin activation. FGFR activation-induced cell proliferation and survival were also inhibited by the compound ICG-001, a small molecule inhibitor of β-catenin-CREB Binding Protein (CBP) in hepatoblasts, further indicating a CBP-dependent regulatory mechanism of β-catenin activity. Conclusion: FGF signaling regulates the proliferation and survival of embryonic and transformed progenitor cells in part through AKT-mediated activation of β-catenin and downstream interaction with the transcriptional co-activator CBP.
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影响因子：
11.4
作者：
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通讯作者：
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