Homeobox protein CDX-1 explained

Homeobox protein CDX-1 is a protein in humans that is encoded by the CDX1 gene.^{[1] [2]} CDX-1 is expressed in the developing endoderm and its expression persists in the intestine throughout adulthood.^[3] CDX-1 protein expression varies along the intestine, with high expression in intestinal crypts and diminishing expression along intestinal villi.^[4]

Function

This gene is a member of the caudal-related homeobox transcription factor family. The encoded DNA-binding protein regulates intestine-specific gene expression and enterocyte differentiation. It has been shown to induce expression of the intestinal alkaline phosphatase gene, and inhibit beta-catenin/T-cell factor transcriptional activity.

CDX1 has also been shown to play an important role in embryonic epicardial development. It has been demonstrated that CDX proteins suppress cardiac differentiation in both zebrafish and mouse embryonic stem cells, but the overall mechanism for how this happens is poorly understood.^[5] However, CDX1 has been shown to be transiently expressed in the embryonic heart 11.5 days post coitum (dpc). This transient expression is thought to induce epicardial epithelial-to-mesenchymal transition and thus proper cardiovascular formation. It has been shown that low-dose CDX1 induction caused enhanced migration and differentiation of epicardium-derived cells into vascular smooth muscle, where as continued high dose induction of CDX1 or CDX1 deficiency diminished the ability of these cells to migrate and differentiate into smooth muscle by the actions of TGF-β1. Furthermore, CDX1 induction also altered transcript expression of genes related to cell adhesions for EMT and angiogenesis.^[6] Therefore, along with its known roles in intestinal patterning and differentiation, CDX1 is also shown to be important in epicardial development.

Further reading

• Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. The Treacher Collins Syndrome Collaborative Group . Nature Genetics . 12 . 2 . 130–136 . February 1996 . 8563749 . 10.1038/ng0296-130 . 34312227 .
• Mallo GV, Rechreche H, Frigerio JM, Rocha D, Zweibaum A, Lacasa M, Jordan BR, Dusetti NJ, Dagorn JC, Iovanna JL . Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis . International Journal of Cancer . 74 . 1 . 35–44 . February 1997 . 9036867 . 10.1002/(SICI)1097-0215(19970220)74:1<35::AID-IJC7>3.0.CO;2-1 . free .
• Mizoshita T, Inada K, Tsukamoto T, Kodera Y, Yamamura Y, Hirai T, Kato T, Joh T, Itoh M, Tatematsu M . Expression of Cdx1 and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa--with special emphasis on participation in intestinal metaplasia of the human stomach . Gastric Cancer . 4 . 4 . 185–191 . 2002 . 11846061 . 10.1007/PL00011741 . free .
• Suh ER, Ha CS, Rankin EB, Toyota M, Traber PG . DNA methylation down-regulates CDX1 gene expression in colorectal cancer cell lines . The Journal of Biological Chemistry . 277 . 39 . 35795–35800 . September 2002 . 12124393 . 10.1074/jbc.M205567200 . free .
• Domon-Dell C, Schneider A, Moucadel V, Guerin E, Guenot D, Aguillon S, Duluc I, Martin E, Iovanna J, Launay JF, Duclos B, Chenard MP, Meyer C, Oudet P, Kedinger M, Gaub MP, Freund JN . Cdx1 homeobox gene during human colon cancer progression . Oncogene . 22 . 39 . 7913–7921 . September 2003 . 12970739 . 10.1038/sj.onc.1206756 . free .
• Wong NA, Britton MP, Choi GS, Stanton TK, Bicknell DC, Wilding JL, Bodmer WF . Loss of CDX1 expression in colorectal carcinoma: promoter methylation, mutation, and loss of heterozygosity analyses of 37 cell lines . Proceedings of the National Academy of Sciences of the United States of America . 101 . 2 . 574–579 . January 2004 . 14704280 . 327189 . 10.1073/pnas.0307190101 . free . 2004PNAS..101..574W .
• Rankin EB, Xu W, Silberg DG, Suh E . Putative intestine-specific enhancers located in 5' sequence of the CDX1 gene regulate CDX1 expression in the intestine . American Journal of Physiology. Gastrointestinal and Liver Physiology . 286 . 5 . G872–G880 . May 2004 . 14715525 . 10.1152/ajpgi.00326.2003 . dead . 18376885 . https://web.archive.org/web/20190307194923/http://pdfs.semanticscholar.org/e620/49c68a417beb919ad5806dd6f10847ceaf43.pdf . 2019-03-07 .
• Béland M, Pilon N, Houle M, Oh K, Sylvestre JR, Prinos P, Lohnes D . Cdx1 autoregulation is governed by a novel Cdx1-LEF1 transcription complex . Molecular and Cellular Biology . 24 . 11 . 5028–5038 . June 2004 . 15143193 . 416402 . 10.1128/MCB.24.11.5028-5038.2004 .
• Guo RJ, Huang E, Ezaki T, Patel N, Sinclair K, Wu J, Klein P, Suh ER, Lynch JP . Cdx1 inhibits human colon cancer cell proliferation by reducing beta-catenin/T-cell factor transcriptional activity . The Journal of Biological Chemistry . 279 . 35 . 36865–36875 . August 2004 . 15215241 . 10.1074/jbc.M405213200 . free .
• Alkhoury F, Malo MS, Mozumder M, Mostafa G, Hodin RA . Differential regulation of intestinal alkaline phosphatase gene expression by Cdx1 and Cdx2 . American Journal of Physiology. Gastrointestinal and Liver Physiology . 289 . 2 . G285–G290 . August 2005 . 15774940 . 10.1152/ajpgi.00037.2005 . dead . 1066204 . https://web.archive.org/web/20190302155247/http://pdfs.semanticscholar.org/9e38/177f5ab5925035aa00d580d90bff7c318768.pdf . 2019-03-02 .
• Wong NA, Wilding J, Bartlett S, Liu Y, Warren BF, Piris J, Maynard N, Marshall R, Bodmer WF . CDX1 is an important molecular mediator of Barrett's metaplasia . Proceedings of the National Academy of Sciences of the United States of America . 102 . 21 . 7565–7570 . May 2005 . 15894614 . 1140438 . 10.1073/pnas.0502031102 . free . 2005PNAS..102.7565W .

Notes and References

1. Bonner CA, Loftus SK, Wasmuth JJ . Isolation, characterization, and precise physical localization of human CDX1, a caudal-type homeobox gene . Genomics . 28 . 2 . 206–211 . July 1995 . 8530027 . 10.1006/geno.1995.1132 .
2. Web site: Entrez Gene: CDX1 caudal type homeobox transcription factor 1.
3. Grainger S, Hryniuk A, Lohnes D . Cdx1 and Cdx2 exhibit transcriptional specificity in the intestine . PLOS ONE . 8 . 1 . e54757 . 2013 . 23382958 . 3559873 . 10.1371/journal.pone.0054757 . free . 2013PLoSO...854757G .
4. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H . Identification of stem cells in small intestine and colon by marker gene Lgr5 . Nature . 449 . 7165 . 1003–1007 . October 2007 . 17934449 . 10.1038/nature06196 . 4349637 . 2007Natur.449.1003B .
5. Lengerke C, Wingert R, Beeretz M, Grauer M, Schmidt AG, Konantz M, Daley GQ, Davidson AJ . Interactions between Cdx genes and retinoic acid modulate early cardiogenesis . Developmental Biology . 354 . 1 . 134–142 . June 2011 . 21466798 . 3502019 . 10.1016/j.ydbio.2011.03.027 .
6. Chu M, Wang L, Wang H, Shen T, Yang Y, Sun Y, Tang N, Ni T, Zhu J, Mailman RB, Wang Y . A novel role of CDX1 in embryonic epicardial development . PLOS ONE . 9 . 7 . e103271 . 2014 . 25068460 . 4113346 . 10.1371/journal.pone.0103271 . free . 2014PLoSO...9j3271C .