γ-Catenin is overexpressed in acute myeloid leukemia and promotes the stabilization and nuclear localization of β-catenin.
γ-Catenin is overexpressed in acute myeloid leukemia and promotes the stabilization and nuclear localization of β-catenin.
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DOI：
10.1038/leu.2012.221
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发表时间：
2013-02
期刊：
影响因子：
11.4
通讯作者：
Darley, R. L.
中科院分区：
文献类型：
--
作者：
Morgan, R. G.;Pearn, L.;Liddiard, K.;Pumford, S. L.;Burnett, A. K.;Tonks, A.;Darley, R. L.
经典Wnt信号转导通过转录共激活因子β-连环蛋白的稳定和核转位来调节T细胞因子（TCF）应答基因的转录。β-连环蛋白的过度表达在急性髓细胞白血病（AML）中具有显著特征，并且先前与不良临床结局相关。γ-连环蛋白mRNA（β-连环蛋白的密切同源物）的过表达也已在AML中被报道，并且与该疾病的发病机制有关，然而，这些连环蛋白在白血病中的相对作用仍不清楚。在这里，我们报告，γ-连环蛋白的过度表达和异常核定位是常见的AML。重要的是，γ-连环蛋白表达与β-连环蛋白稳定性和核定位相关。与此一致，我们发现异位γ-catenin表达促进白血病细胞中β-catenin的稳定和核转位。β-连环蛋白敲低表明γ-和β-连环蛋白都有助于白血病细胞中TCF依赖性转录。这些数据表明，γ-连环蛋白表达是AML中β-连环蛋白稳定化的重要因素。我们还发现，尽管正常细胞排除γ-和β-连环蛋白的核转位，但这种调节水平在大多数AML患者和细胞系中丢失，这使得这些连环蛋白和不适当的TCF依赖性转录在核中积聚。
Canonical Wnt signaling regulates the transcription of T-cell factor (TCF)-responsive genes through the stabilization and nuclear translocation of the transcriptional co-activator, β-catenin. Overexpression of β-catenin features prominently in acute myeloid leukemia (AML) and has previously been associated with poor clinical outcome. Overexpression of γ-catenin mRNA (a close homologue of β-catenin) has also been reported in AML and has been linked to the pathogenesis of this disease, however, the relative roles of these catenins in leukemia remains unclear. Here we report that overexpression and aberrant nuclear localization of γ-catenin is frequent in AML. Significantly, γ-catenin expression was associated with β-catenin stabilization and nuclear localization. Consistent with this, we found that ectopic γ-catenin expression promoted the stabilization and nuclear translocation of β-catenin in leukemia cells. β-Catenin knockdown demonstrated that both γ- and β-catenin contribute to TCF-dependent transcription in leukemia cells. These data indicate that γ-catenin expression is a significant factor in the stabilization of β-catenin in AML. We also show that although normal cells exclude nuclear translocation of both γ- and β-catenin, this level of regulation is lost in the majority of AML patients and cell lines, which allow nuclear accumulation of these catenins and inappropriate TCF-dependent transcription.
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影响因子：
11.4
作者：
通讯作者：
--
DOI：
10.1083/jcb.123.6.1857
发表时间：
1993-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bradley RS;Cowin P;Brown AM
通讯作者：
Brown AM
影响因子：
11.4
作者：
Kajiguchi, T.;Chung, E. J.;Trepel, J. B.
通讯作者：
Trepel, J. B.
影响因子：
158.5
作者：
Jamieson, CHM;Ailles, LE;Weissman, IL
通讯作者：
Weissman, IL
影响因子：
9.2
作者：
Fagotto, F;Glück, U;Gumbiner, BM
通讯作者：
Gumbiner, BM