Activation of AXIN2 expression by β-catenin-T cell factor -: A feedback repressor pathway regulating Wnt signaling
Activation of AXIN2 expression by β-catenin-T cell factor -: A feedback repressor pathway regulating Wnt signaling
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DOI：
10.1074/jbc.m200139200
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发表时间：
2002-06-14
影响因子：
4.8
通讯作者：
Fearon, ER
中科院分区：
文献类型：
--
作者：
Leung, JY;Kolligs, FT;Fearon, ER
Wnt通路调控细胞的命运、增殖和凋亡，而该通路中的缺陷在许多癌症中起着关键作用。虽然WNTs的作用是稳定胞浆和细胞核中的β-catenin水平，但含有腺瘤性息肉病结肠、糖原合成酶激酶3beta和Axin1或其同系物Axin2/Axil/conductin的多蛋白复合体促进β-catenin的磷酸化和随后的蛋白酶体降解。我们发现，在突变的β-连环蛋白或γ-连环蛋白对RK3E细胞的肿瘤转化过程中，或在配体诱导的β-连环蛋白-雌激素受体融合蛋白激活之后，大鼠Axil基因被强烈诱导。WNT1在小鼠乳腺上皮细胞中的表达激活了传导素基因，而β-连环素调节缺陷的人类癌症则上调了AXIN2基因和蛋白的表达。通过恢复野生型腺瘤性息肉病结肠功能或表达显性阴性形式的T细胞因子(TCF)-4，AXIN2/Axil的表达在癌细胞中受到强烈抑制。AXIN2启动子中的Tcf结合位点在β-catenin激活AXIN2转录的能力中起着关键作用。与AXIN2/Axil不同，人或大鼠Axin1同源基因的表达在名义上受到β-catenin-TCF的影响。由于Axin2可以抑制β-连环素的丰度和功能，该数据暗示AXIN2参与了调节Wnt信号的负反馈途径。此外，尽管Axin1和Axin2被认为具有类似的功能，但观察到Wnt途径激活可上调AXIN2而不是AXIN1的表达，这表明这两种蛋白之间可能存在潜在的显著功能差异。
The Wnt pathway regulates cell fate, proliferation, and apoptosis, and defects in the pathway play a key role in many cancers. Although Wnts act to stabilize beta-catenin levels in the cytosol and nucleus, a multiprotein complex containing adenomatous polyposis coli, glycogen synthase kinase 3beta, and Axin1 or its homolog Axin2/Axil/conductin promotes beta-catenin phosphorylation and subsequent proteasomal degradation. We found that the rat Axil gene was strongly induced upon neoplastic transformation of RK3E cells by mutant beta-catenin or gamma-catenin or after ligand-induced activation of a beta-catenin-estrogen receptor fusion protein. Expression of Wnt1 in murine breast epithelial cells activated the conductin gene, and human cancers with defective beta-catenin regulation had elevated AXIN2 gene and protein expression. Expression of AXIN2/Axil was strongly repressed in cancer cells by restoration of wild type adenomatous polyposis coli function or expression of a dominant negative form of T cell factor (TCF)-4. TCF binding sites in the AXIN2 promoter played a key role in the ability of beta-catenin to activate AXIN2 transcription. In contrast to AXIN2/Axil, expression of human or rat Axin1 homologs was nominally affected by beta-catenin-TCF. Because Axin2 can inhibit beta-catenin abundance and function, the data implicate AXIN2 in a negative feedback pathway regulating Wnt signaling. Additionally, although Axin1 and Axin2 have been thought to have comparable functions, the observation that Wnt pathway activation elevates AXIN2 but not AXIN1 expression suggests that there may be potentially significant functional differences between the two proteins.