Journal
CELLULAR SIGNALLING
Volume 21, Issue 12, Pages 1846-1856Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2009.07.020
Keywords
Cdx2; Colorectal cancer; PKC; Raf-1; ERK; TS cells
Categories
Funding
- BBSRC
- Babraham Institute
- BBSRC [BBS/E/B/0000C230, BBS/E/B/0000C162, BBS/E/B/0000C224, BBS/E/B/0000C225] Funding Source: UKRI
- MRC [G120/824, G0800784] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C230, BBS/E/B/0000C224, BBS/E/B/0000C162, BBS/E/B/0000C225] Funding Source: researchfish
- Medical Research Council [G0800784, G0800784B, G120/824] Funding Source: researchfish
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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 turnout 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 Delta Raf-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 turnout suppressor by linking it to ERK1/2, a pathway which is frequently activated in CRC. (C) 2009 Elsevier Inc. All rights reserved.
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