The MIF homologue D-dopachrome tautomerase promotes COX-2 expression through β-catenin-dependent and -independent mechanisms.
The MIF homologue D-dopachrome tautomerase promotes COX-2 expression through β-catenin-dependent and -independent mechanisms.
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DOI：
10.1158/1541-7786.mcr-10-0101
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Mitchell RA
中科院分区：
文献类型：
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作者：
Xin D;Rendon BE;Zhao M;Winner M;McGhee Coleman A;Mitchell RA
细胞因子/生长因子、巨噬细胞迁移抑制因子（MIF）促成与免疫、炎症和肿瘤疾病过程相关的病理。一些研究已经证明了MIF依赖性环氧合酶-2（考克斯-2）表达在这些疾病的进展中的重要贡献作用。我们现在报告，MIF同源物，D-多巴色素互变异构酶（D-DT），是足够的和必要的最大考克斯-2表达在结直肠腺癌细胞系。D-DT依赖性考克斯-2转录部分由β-catenin蛋白稳定化和随后的转录介导。c-jun-N-末端激酶（JNK）和MIF相互作用蛋白Jab 1/CSN 5的活性也有助于D-DT调节考克斯-2表达。有趣的是，发现D-DT依赖的β-连环蛋白稳定化受考克斯-2表达的调节，表明在这些细胞中存在考克斯-2和β-连环蛋白介导的转录之间的扩增环。由于考克斯-2和β-连环蛋白介导的转录都是结直肠癌（CRC）疾病维持和进展的重要因素，这些发现表明MIF家族成员在CRC发病机制中具有独特和新颖的调节作用。
The cytokine/growth factor, macrophage migration inhibitory factor (MIF) contributes to pathologies associated with immune, inflammatory and neoplastic disease processes. Several studies have demonstrated an important contributing role for MIF-dependent cyclooxygenase-2 (COX-2) expression in the progression of these disorders. We now report that the MIF homolog, D-dopachrome tautomerase (D-DT), is both sufficient and necessary for maximal COX-2 expression in colorectal adenocarcinoma cell lines. D-DT-dependent COX-2 transcription is mediated in part by β-catenin protein stabilization and subsequent transcription. Also contributing to D-DTs regulation of COX-2 expression are the activities of both c-jun-N-terminal kinase (JNK) and the MIF-interacting protein, Jab1/CSN5. Interestingly, D-DT-dependent β-catenin stabilization was found to be regulated by COX-2 expression suggesting the existence of an amplification loop between COX-2 and β-catenin-mediated-transcription in these cells. Because both COX-2 and β-catenin-mediated transcription are important contributors to colorectal cancer (CRC) disease maintenance and progression, these findings suggest a unique and novel regulatory role for MIF family members in CRC pathogenesis.