Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan, Republic of China.
J Cell Biochem. 2010 Oct 1;111(2):402-11. doi: 10.1002/jcb.22714.
The Wnt/β-catenin pathway has been implicated in leukemogenesis. We found β-catenin abnormally accumulated in both human acute T cell leukemia Jurkat cells and human erythroleukemia HEL cells. β-Catenin can be significantly down-regulated by the Janus kinase 2 specific inhibitor AG490 in these two cells. AG490 also reduces the luciferase activity of a reporter plasmid driven by LEF/β-catenin promoter. Similar results were observed in HEL cells infected with lentivirus containing shRNA against JAK2 gene. After treatment with 50 µM AG490 or shRNA, the mRNA expression levels of β-catenin, APC, Axin, β-Trcp, GSK3α, and GSK3β were up-regulated within 12-16 h. However, only the protein levels of GSK3β and β-Trcp were found to have increased relative to untreated cells. Knockdown experiments revealed that the AG490-induced inhibition of β-catenin can be attenuated by shRNA targeting β-TrCP. Taken together; these results suggest that β-Trcp plays a key role in the cross-talk between JAK/STAT and Wnt/β-catenin signaling in leukemia cells.
Wnt/β-catenin 通路与白血病的发生有关。我们发现β-catenin 在人急性 T 细胞白血病 Jurkat 细胞和人红白血病 HEL 细胞中异常积累。Janus 激酶 2（JAK2）特异性抑制剂 AG490 可显著下调这两种细胞中的β-catenin。AG490 还降低了由 LEF/β-catenin 启动子驱动的报告质粒的荧光素酶活性。在感染了含有 JAK2 基因 shRNA 的慢病毒的 HEL 细胞中观察到了类似的结果。用 50µM AG490 或 shRNA 处理后，β-catenin、APC、Axin、β-Trcp、GSK3α 和 GSK3β 的 mRNA 表达水平在 12-16 小时内上调。然而，仅发现 GSK3β 和 β-Trcp 的蛋白水平与未处理的细胞相比有所增加。敲低实验表明，针对β-TrCP 的 shRNA 可减弱 AG490 诱导的β-catenin 抑制。综上所述，这些结果表明β-TrCP 在白血病细胞中 JAK/STAT 和 Wnt/β-catenin 信号通路的串扰中起关键作用。
