Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
J Cell Sci. 2010 May 15;123(Pt 10):1716-23. doi: 10.1242/jcs.062661. Epub 2010 Apr 20.
Alteration of protein trafficking and localization is associated with several diseases, including cystic fibrosis, breast cancer, colorectal cancer, leukemia and diabetes. Specifically, aberrant nuclear localization of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is a poor prognostic indicator in several epithelial carcinomas. It is now appreciated that in addition to signaling from the plasma membrane, EGFR also trafficks to the nucleus, and can directly bind the promoter regions of genes encoding cyclin D1 (CCND1) and B-Myb (MYBL2). We have previously established that loss of MUC1 in an EGFR-dependent transgenic mouse model of breast cancer correlates with the loss of cyclin D1 expression. Here, we provide evidence for a novel regulatory function of MUC1 in the trafficking and nuclear activity of EGFR. We found that MUC1 and EGFR interact in the nucleus of breast cancer cells, which promotes the accumulation of chromatin-bound EGFR. Additionally, the presence of MUC1 results in significant colocalization of EGFR and phosphorylated RNA polymerase II, indicating that MUC1 influences the association of EGFR with transcriptionally active promoter regions. Importantly, we found that the loss of MUC1 expression resulted in a decrease in the interaction between EGFR and the CCND1 promoter, which translated to a significant decrease in cyclin D1 protein expression. This data offers insights into a novel regulatory mechanism of EGFR nuclear function and could have important implications for evaluating nuclear localization in cancer.
蛋白质运输和定位的改变与多种疾病有关，包括囊性纤维化、乳腺癌、结直肠癌、白血病和糖尿病。具体来说，表皮生长因子受体（EGFR）的核定位异常，EGFR 是一种受体酪氨酸激酶，是几种上皮癌预后不良的指标。现在人们已经认识到，除了来自质膜的信号外，EGFR 还会运输到细胞核，并可以直接结合编码细胞周期蛋白 D1（CCND1）和 B-Myb（MYBL2）的基因的启动子区域。我们之前已经确定，在 EGFR 依赖性转基因乳腺癌小鼠模型中 MUC1 的缺失与细胞周期蛋白 D1 表达的缺失相关。在这里，我们提供了 MUC1 在 EGFR 运输和核活性中的新调节功能的证据。我们发现 MUC1 和 EGFR 在乳腺癌细胞的核内相互作用，这促进了染色质结合的 EGFR 的积累。此外，MUC1 的存在导致 EGFR 和磷酸化 RNA 聚合酶 II 的显著共定位，表明 MUC1 影响 EGFR 与转录活性启动子区域的结合。重要的是，我们发现 MUC1 表达的缺失导致 EGFR 与 CCND1 启动子之间的相互作用减少，这转化为细胞周期蛋白 D1 蛋白表达的显著减少。这些数据提供了对 EGFR 核功能的新调节机制的深入了解，并且可能对评估癌症中的核定位具有重要意义。
