Micsenyi Amanda, Tan Xinping, Sneddon Tamara, Luo Jian-Hua, Michalopoulos George K, Monga Satdarshan P S
Department of Pathology, University of Pittsburgh, School of Medicine, PA 15261, USA.
Gastroenterology. 2004 Apr;126(4):1134-46. doi: 10.1053/j.gastro.2003.12.047.
BACKGROUND & AIMS: beta-Catenin, a key component of the Wnt pathway, plays an important role in unregulated liver growth in liver tumors, in regulated growth during liver regeneration, and in ex vivo embryonic liver cultures.
We used developing livers from several stages of gestational development to examine beta-catenin expression, protein-protein interactions, localization, and regulation in prenatal and postnatal livers.
Microarray, Northern, and protein analyses showed peak expression of beta-catenin during early liver development at Embryonic day 10 (E10)-E12, followed by a decrease and a complete loss of normal beta-catenin (97-kilodalton species) after E16 through the remaining prenatal period. At the early stages, beta-catenin localized to the cytoplasm and nuclei of resident cells in addition to its normal membranous localization, which was seen at all later stages and in adult liver. Decreases in beta-catenin levels at E14 onward coincided with its decreased gene expression and increased degradation, as seen by an increase in serine 45/threonine 41-phosphorylated beta-catenin and its other negative regulators, such as axin, adenomatous polyposis coli gene product (APC), and glycogen synthase kinase-3 beta. Finally, we showed an intact association of E-cadherin and beta-catenin despite the loss of beta-catenin at E16-E18, owing to the presence of membrane-associated smaller-molecular-weight beta-catenin species.
We also identified a stage-specific expression and regulation of beta-catenin during liver development that might be crucial for physiological liver development. Nuclear and cytoplasmic beta-catenin corresponded to cell proliferation in liver development. Finally, a smaller-molecular-weight species of beta-catenin might be maintaining normal interactions at the membrane.
β-连环蛋白是Wnt信号通路的关键组成部分，在肝肿瘤中肝脏的无节制生长、肝脏再生过程中的生长调节以及体外胚胎肝脏培养中均发挥重要作用。
我们使用来自妊娠发育几个阶段的发育中的肝脏，来检测β-连环蛋白在产前和产后肝脏中的表达、蛋白质-蛋白质相互作用、定位及调控情况。
微阵列、Northern印迹和蛋白质分析显示，β-连环蛋白在胚胎第10天（E10）至E12的肝脏早期发育阶段表达达到峰值，随后下降，在E16之后直至整个产前阶段正常的β-连环蛋白（97千道尔顿形式）完全消失。在早期阶段，β-连环蛋白除了正常的膜定位外，还定位于驻留细胞的细胞质和细胞核，这种膜定位在所有后期阶段及成年肝脏中均可看到。从E14起β-连环蛋白水平的下降与其基因表达的降低和降解的增加相一致，这可通过丝氨酸45/苏氨酸41磷酸化的β-连环蛋白及其其他负调控因子（如axin、腺瘤性息肉病结肠基因产物（APC）和糖原合酶激酶-3β）的增加来体现。最后，尽管在E16 - E18时β-连环蛋白缺失，但由于存在膜相关的较小分子量β-连环蛋白形式，我们发现E-钙黏蛋白和β-连环蛋白仍保持完整的结合。
我们还确定了肝脏发育过程中β-连环蛋白的阶段特异性表达和调控，这可能对生理性肝脏发育至关重要。核内和胞质中的β-连环蛋白与肝脏发育中的细胞增殖相对应。最后，较小分子量的β-连环蛋白形式可能维持了膜上的正常相互作用。
