Gu Wei, Wells Amber L, Pan Feng, Singer Robert H
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Mol Cell Biol. 2008 Aug;28(16):4963-74. doi: 10.1128/MCB.00266-08. Epub 2008 May 19.
ZBP1 (zipcode binding protein 1) is an RNA-binding protein involved in many posttranscriptional processes, such as RNA localization, RNA stability, and translational control. ZBP1 is abundantly expressed in embryonic development, but its expression is silenced in most adult tissues. Reactivation of the ZBP1 gene has been reported in various human tumors. In this study, we identified a detailed molecular mechanism of ZBP1 transactivation in breast cancer cells. We show that beta-catenin, a protein that functions in both cell adhesion and transcription, specifically binds to the ZBP1 promoter via a conserved beta-catenin/TCF4 response element and activates its gene expression. ZBP1 activation is also closely correlated with nuclear translocation of beta-catenin in human breast tumors. We further demonstrate feedback regulation by finding that ZBP1 physically associates with beta-catenin mRNA in vivo and increases its stability. These experiments suggest that in breast cancer cells, the expression of ZBP1 and the expression of beta-catenin are coordinately regulated. beta-Catenin mediates the transcription of the ZBP1 gene, while ZBP1 promotes the stability of beta-catenin mRNA.
ZBP1（邮政编码结合蛋白1）是一种RNA结合蛋白，参与许多转录后过程，如RNA定位、RNA稳定性和翻译控制。ZBP1在胚胎发育中大量表达，但其表达在大多数成年组织中沉默。ZBP1基因的重新激活已在各种人类肿瘤中报道。在本研究中，我们确定了乳腺癌细胞中ZBP1反式激活的详细分子机制。我们发现，β-连环蛋白，一种在细胞黏附和转录中都起作用的蛋白质，通过保守的β-连环蛋白/TCF4反应元件特异性结合ZBP1启动子并激活其基因表达。ZBP1激活也与人类乳腺肿瘤中β-连环蛋白的核转位密切相关。我们进一步通过发现ZBP1在体内与β-连环蛋白mRNA物理结合并增加其稳定性来证明反馈调节。这些实验表明，在乳腺癌细胞中，ZBP1的表达和β-连环蛋白的表达是协同调节的。β-连环蛋白介导ZBP1基因的转录，而ZBP1促进β-连环蛋白mRNA的稳定性。
