β-catenin and Tcfs in mammary development and cancer
β-catenin and Tcfs in mammary development and cancer
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DOI：
10.1023/a:1025944723047
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发表时间：
2003-04-01
影响因子：
2.5
通讯作者：
Cowin, P
中科院分区：
文献类型：
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作者：
Hatsell, S;Rowlands, T;Cowin, P
β-连环蛋白调节细胞-细胞粘附并从许多途径转导信号以调节Tcf/Lef DNA结合因子的转录活性。基因切除和转基因表达研究强烈支持这样的概念，即β-连环蛋白与Lef/Tcf因子一起作为一个开关来决定细胞命运，并在乳腺发育的几个阶段促进细胞存活和增殖。表达Wnt/β-连环蛋白信号传导负调节因子（K14-Dkk）的小鼠不能形成乳腺芽，而缺乏Lef-1的小鼠在E13.5期显示出该过程的早期停滞。稳定的DeltaN 89 β-连环蛋白在青春期发育期间启动早熟的肺泡发生，内源性β-连环蛋白信号传导的负调节剂在妊娠期间抑制正常的肺泡发生。稳定的β-连环蛋白在小鼠中诱导增生和乳腺肿瘤。每种β-连环蛋白诱导的表型都伴随着靶基因细胞周期蛋白D1和c-myc的上调。然而，细胞周期蛋白D1对于肿瘤的形成和肺泡形成的起始是不可缺少的，但对于以后的肺泡扩张是必不可少的。
beta-Catenin regulates cell-cell adhesion and transduces signals from many pathways to regulate the transcriptional activities of Tcf/Lef DNA binding factors. Gene ablation and transgenic expression studies strongly support the concept that beta-catenin together with Lef/Tcf factors act as a switch to determine cell fate and promote cell survival and proliferation at several stages during mammary gland development. Mice expressing the negative regulator of Wnt/beta-catenin signaling (K14-Dkk) fail to form mammary buds, and those lacking Lef-1 show an early arrest in this process at stage E13.5. Stabilized DeltaN89beta-catenin initiates precocious alveologenesis- during pubertal development, and negative regulators of endogenous beta-catenin signaling suppress normal alveologenesis during pregnancy. Stabilized beta-catenin induces hyperplasia and mammary tumors in mice. Each of the beta-catenin-induced phenotypes is accompanied by upregulation of the target genes cyclin D1 and c-myc. Cyclin D1, however, is dispensable for tumor formation and the initiation of alveologenesis but is essential for later alveolar expansion.