Howe L R, Crawford H C, Subbaramaiah K, Hassell J A, Dannenberg A J, Brown A M
Department of Cell Biology and Anatomy, Weill Medical College of Cornell University, New York, New York 10021, USA.
J Biol Chem. 2001 Jun 8;276(23):20108-15. doi: 10.1074/jbc.M010692200. Epub 2001 Mar 26.
The inducible prostaglandin synthase cyclooxygenase-2 (COX-2) is aberrantly expressed in intestinal tumors resulting from APC mutation, and is also transcriptionally up-regulated in mouse mammary epithelial cells in response to Wnt1 expression. beta-Catenin stabilization is a consequence of both APC mutation and Wnt signaling. We have previously observed coordinate regulation of the matrilysin promoter by beta-catenin and Ets family transcription factors of the PEA3 subfamily. Here we show that while beta-catenin only weakly activates the COX-2 promoter, PEA3 family transcription factors are potent activators of COX-2 transcription. Consistent with this, PEA3 is up-regulated in Wnt1-expressing mouse mammary epithelial cells, and PEA3 factors are highly expressed in tumors from Wnt1 transgenic mice, in which Cox-2 is also up-regulated. Promoter mapping experiments suggest that the NF-IL6 site in the COX-2 promoter is important for mediating PEA3 responsiveness. The NF-IL6 site is also important for COX-2 transcription in some colorectal cancer lines (Shao, J., Sheng, H., Inoue, H., Morrow, J. D., and DuBois, R. N. (2000) J. Biol. Chem. 275, 33951-33956), and PEA3 factors are highly expressed in colorectal cancer cell lines. Therefore, we speculate that PEA3 factors may contribute to the up-regulation of COX-2 expression resulting from both APC mutation and Wnt1 expression.
诱导型前列腺素合酶环氧化酶-2（COX-2）在因APC突变导致的肠道肿瘤中异常表达，并且在小鼠乳腺上皮细胞中，其转录也会因Wnt1表达而上调。β-连环蛋白的稳定是APC突变和Wnt信号传导的共同结果。我们之前观察到，β-连环蛋白和PEA3亚家族的Ets家族转录因子对基质溶素启动子具有协同调节作用。在此我们表明，虽然β-连环蛋白仅能微弱激活COX-2启动子，但PEA3家族转录因子却是COX-2转录的强效激活剂。与此一致的是，PEA3在表达Wnt1的小鼠乳腺上皮细胞中上调，并且在Wnt1转基因小鼠的肿瘤中高度表达，在这些肿瘤中Cox-2也上调。启动子定位实验表明，COX-2启动子中的NF-IL6位点对于介导PEA3反应性很重要。NF-IL6位点在某些结直肠癌系中对于COX-2转录也很重要（邵，J.，盛，H.，井上，H.，莫罗，J.D.，和杜波依斯，R.N.（2000年）《生物化学杂志》275，33951 - 33956），并且PEA3因子在结直肠癌细胞系中高度表达。因此，我们推测PEA3因子可能促成了因APC突变和Wnt1表达导致的COX-2表达上调。
