Down-regulation of Cdx2 in colorectal carcinoma cells by the Raf-MEK-ERK 1/2 pathway.
Down-regulation of Cdx2 in colorectal carcinoma cells by the Raf-MEK-ERK 1/2 pathway.
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Raf-MEK-ERK 1/2途径下调结直肠癌细胞中的Cdx2。
DOI：
10.1016/j.cellsig.2009.07.020
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发表时间：
2009-12
影响因子：
4.8
通讯作者：
Gaunt SJ
中科院分区：
文献类型：
--
作者：
Krueger F;Madeja Z;Hemberger M;McMahon M;Cook SJ;Gaunt SJ
Cdx 2是一种调节正常肠细胞分化的同源域转录因子。Cdx 2在结直肠癌（CRC）进展过程中经常丢失，被广泛认为是结直肠肿瘤抑制因子。先前的研究表明，蛋白激酶C（PKC）的激活可能是CRC细胞中Cdx 2下调的原因。在这里，我们表明，激活PKC确实促进下调Cdx 2在mRNA和蛋白质水平。然而，Cdx 2的PKC依赖性损失依赖于Raf-MEK-ERK 1/2通路的激活。事实上，使用条件激酶ΔRaf-1：ER特异性激活ERK 1/2通路足以抑制Cdx 2转录。由于K-Ras的突变，Raf-MEK-ERK 1/2通路在大部分结直肠癌中被过度激活，我们表明用MEK抑制剂治疗CRC细胞系会导致Cdx 2表达增加。此外，ERK 1/2通路的激活促进Cdx 2蛋白的磷酸化和蛋白酶体依赖性降解。ERK 1/2对CRC细胞中Cdx 2的抑制作用与其对滋养外胚层和滋养层干细胞中Cdx 2表达的刺激作用形成鲜明对比。这些结果通过将Cdx 2与ERK 1/2（一种在CRC中经常被激活的途径）联系起来，为Cdx 2肿瘤抑制因子的调控提供了重要的新见解。
Cdx2 is a homeodomain transcription factor that regulates normal intestinal cell differentiation. Cdx2 is frequently lost during progression of colorectal cancer (CRC) and is widely viewed as a colorectal tumour suppressor. A previous study suggested that activation of protein kinase C (PKC) may be responsible for Cdx2 down-regulation in CRC cells. Here we show that activation of PKC does indeed promote down-regulation of Cdx2 at both the mRNA and protein levels. However, PKC-dependent loss of Cdx2 is dependent upon activation of the Raf–MEK–ERK1/2 pathway. Indeed, specific activation of the ERK1/2 pathway using the conditional kinase ΔRaf-1:ER is sufficient to inhibit Cdx2 transcription. The Raf–MEK–ERK1/2 pathway is hyper-activated in a large fraction of colorectal cancers due to mutations in K-Ras and we show that treatment of CRC cell lines with MEK inhibitors causes an increase in Cdx2 expression. Furthermore, activation of the ERK1/2 pathway promotes the phosphorylation and proteasome-dependent degradation of the Cdx2 protein. The inhibitory effect of ERK1/2 upon Cdx2 in CRC cells is in sharp contrast to its stimulatory effect upon Cdx2 expression in trophectoderm and trophoblast stem cells. These results provide important new insights into the regulation of the Cdx2 tumour suppressor by linking it to ERK1/2, a pathway which is frequently activated in CRC.