Homeobox protein CDX-2 explained

Homeobox protein CDX-2 is a protein that in humans is encoded by the CDX2 gene. The CDX-2 protein is a homeobox transcription factor expressed in the nuclei of intestinal epithelial cells,^[1] playing an essential role in the development and function of the digestive system. CDX2 is part of the ParaHox gene cluster, a group of three highly conserved developmental genes present in most vertebrate species.^[2] Together with CDX1 and CDX4, CDX2 is one of three caudal-related genes in the human genome.

Function

In common with the two other Cdx genes, CDX2 regulates several essential processes in the development and function of the lower gastrointestinal tract (from the duodenum to the anus) in vertebrates. In vertebrate embryonic development, CDX2 becomes active in endodermal cells that are posterior to the developing stomach.^[3] These cells eventually form the intestinal epithelium. The activity of CDX2 at this stage is essential for the correct formation of the intestine and the anus.^{[4] [5]} CDX2 is also required for the development of the placenta.

Later in development, CDX2 is expressed in intestinal epithelial stem cells, which are cells that continuously differentiate into the cells that form the intestinal lining. This differentiation is dependent on CDX2,^{[6] [7]} as illustrated by experiments where the expression of this gene was knocked-out or overexpressed in mice. Heterozygous CDX2 knock-outs have intestinal lesions caused by the differentiation of intestinal cells into gastric epithelium; this can be considered a form of homeotic transformation.^[8] Conversely, the over-expression of CDX2 leads to the formation of intestinal epithelium in the stomach.^[9]

In addition to roles in endoderm, CDX2 is also expressed in very early stages of mouse and human embryonic development, specifically marking the trophectoderm lineage of cells in the blastocyst of mouse and human. Trophectoderm cells contribute to the placenta.

Pathology

Ectopic expression of CDX2 was reported in more than 85% of the human patients with acute myeloid leukemia (AML). Ectopic expression of Cdx2 in murine bone marrow induced AML in mice and upregulate Hox genes in bone marrow progenitors.^{[10] [11]} CDX2 is also implicated in the pathogenesis of Barrett's esophagus where it has been shown that components from gastroesophageal reflux such as bile acids are able to induce the expression of an intestinal differentiation program through up-regulation of NF-κB and CDX2.^[12]

Biomarker for intestinal cancer

CDX2 is also used in diagnostic surgical pathology as a marker for gastrointestinal differentiation, especially colorectal.^[13]

Possible use in stem cell research

This gene (or, more specifically, the equivalent gene in humans) has come up in the proposal by the President's Council on Bioethics, as a solution to the stem cell controversy.^[14] According to one of the plans put forth, by deactivating the gene, it would not be possible for a properly organized embryo to form, thus providing stem cells without requiring the destruction of an embryo.^[15] Other genes that have been proposed for this purpose include Hnf4, which is required for gastrulation.^{[14] [16]}

Interactions

CDX2 has been shown to interact with EP300,^[17] and PAX6.^[17]

Further reading

• Suh E, Chen L, Taylor J, Traber PG . A homeodomain protein related to caudal regulates intestine-specific gene transcription . Molecular and Cellular Biology . 14 . 11 . 7340–7351 . November 1994 . 7935448 . 359269 . 10.1128/mcb.14.11.7340 .
• Inoue H, Riggs AC, Tanizawa Y, Ueda K, Kuwano A, Liu L, Donis-Keller H, Permutt MA . Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene . Diabetes . 45 . 6 . 789–794 . June 1996 . 8635654 . 10.2337/diabetes.45.6.789 . Helen Donis-Keller .
• 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 . 46416077 .
• Chawengsaksophak K, James R, Hammond VE, Köntgen F, Beck F . Homeosis and intestinal tumours in Cdx2 mutant mice . Nature . 386 . 6620 . 84–87 . March 1997 . 9052785 . 10.1038/386084a0 . 4252265 . 1997Natur.386...84C .
• Walters JR, Howard A, Rumble HE, Prathalingam SR, Shaw-Smith CJ, Legon S . Differences in expression of homeobox transcription factors in proximal and distal human small intestine . Gastroenterology . 113 . 2 . 472–477 . August 1997 . 9247466 . 10.1053/gast.1997.v113.pm9247466 . free .
• Drummond F, Putt W, Fox M, Edwards YH . Cloning and chromosome assignment of the human CDX2 gene . Annals of Human Genetics . 61 . Pt 5 . 393–400 . September 1997 . 9459001 . 10.1046/j.1469-1809.1997.6150393.x . 45461007 . free .
• Yamamoto H, Miyamoto K, Li B, Taketani Y, Kitano M, Inoue Y, Morita K, Pike JW, Takeda E . The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine . Journal of Bone and Mineral Research . 14 . 2 . 240–247 . February 1999 . 9933478 . 10.1359/jbmr.1999.14.2.240 . 45176819 .
• Hussain MA, Habener JF . Glucagon gene transcription activation mediated by synergistic interactions of pax-6 and cdx-2 with the p300 co-activator . The Journal of Biological Chemistry . 274 . 41 . 28950–28957 . October 1999 . 10506141 . 10.1074/jbc.274.41.28950 . free .
• Mitchelmore C, Troelsen JT, Spodsberg N, Sjöström H, Norén O . Interaction between the homeodomain proteins Cdx2 and HNF1alpha mediates expression of the lactase-phlorizin hydrolase gene . The Biochemical Journal . 346 . Pt 2 . 529–535 . March 2000 . 10677375 . 1220882 . 10.1042/0264-6021:3460529 .
• Sivagnanasundaram S, Islam I, Talbot I, Drummond F, Walters JR, Edwards YH . The homeobox gene CDX2 in colorectal carcinoma: a genetic analysis . British Journal of Cancer . 84 . 2 . 218–225 . January 2001 . 11161380 . 2363702 . 10.1054/bjoc.2000.1544 .
• Rings EH, Boudreau F, Taylor JK, Moffett J, Suh ER, Traber PG . Phosphorylation of the serine 60 residue within the Cdx2 activation domain mediates its transactivation capacity . Gastroenterology . 121 . 6 . 1437–1450 . December 2001 . 11729123 . 10.1053/gast.2001.29618 . free .
• Hinoi T, Tani M, Lucas PC, Caca K, Dunn RL, Macri E, Loda M, Appelman HD, Cho KR, Fearon ER . Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon . The American Journal of Pathology . 159 . 6 . 2239–2248 . December 2001 . 11733373 . 1850596 . 10.1016/S0002-9440(10)63074-X .
• 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 .
• Eda A, Osawa H, Yanaka I, Satoh K, Mutoh H, Kihira K, Sugano K . Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia . Journal of Gastroenterology . 37 . 2 . 94–100 . 2002 . 11871772 . 10.1007/s005350200002 . 20514893 .
• Qualtrough D, Hinoi T, Fearon E, Paraskeva C . Expression of CDX2 in normal and neoplastic human colon tissue and during differentiation of an in vitro model system . Gut . 51 . 2 . 184–190 . August 2002 . 12117877 . 1773308 . 10.1136/gut.51.2.184 .
• Moucadel V, Totaro MS, Dell CD, Soubeyran P, Dagorn JC, Freund JN, Iovanna JL . The homeobox gene Cdx1 belongs to the p53-p21(WAF)-Bcl-2 network in intestinal epithelial cells . Biochemical and Biophysical Research Communications . 297 . 3 . 607–615 . September 2002 . 12270138 . 10.1016/S0006-291X(02)02250-7 .
• Song BL, Qi W, Wang CH, Yang JB, Yang XY, Lin ZX, Li BL . Preparation of an anti-Cdx-2 antibody for analysis of different species Cdx-2 binding to acat2 promoter . Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao Acta Biochimica et Biophysica Sinica . 35 . 1 . 6–12 . January 2003 . 12518221 .

Notes and References

1. German MS, Wang J, Fernald AA, Espinosa R, Le Beau MM, Bell GI . Localization of the genes encoding two transcription factors, LMX1 and CDX3, regulating insulin gene expression to human chromosomes 1 and 13 . Genomics . 24 . 2 . 403–404 . November 1994 . 7698771 . 10.1006/geno.1994.1639 .
2. Brooke NM, Garcia-Fernàndez J, Holland PW . The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster . Nature . 392 . 6679 . 920–922 . April 1998 . 9582071 . 10.1038/31933 . 4398740 . 1998Natur.392..920B .
3. Beck F, Erler T, Russell A, James R . Expression of Cdx-2 in the mouse embryo and placenta: possible role in patterning of the extra-embryonic membranes . Developmental Dynamics . 204 . 3 . 219–227 . November 1995 . 8573715 . 10.1002/aja.1002040302 . 19576530 .
4. Chawengsaksophak K, James R, Hammond VE, Köntgen F, Beck F . Homeosis and intestinal tumours in Cdx2 mutant mice . Nature . 386 . 6620 . 84–87 . March 1997 . 9052785 . 10.1038/386084a0 . 4252265 . 1997Natur.386...84C .
5. Chawengsaksophak K, de Graaff W, Rossant J, Deschamps J, Beck F . Cdx2 is essential for axial elongation in mouse development . Proceedings of the National Academy of Sciences of the United States of America . 101 . 20 . 7641–7645 . May 2004 . 15136723 . 419659 . 10.1073/pnas.0401654101 . 2004PNAS..101.7641C . free .
6. Simmini S, Bialecka M, Huch M, Kester L, van de Wetering M, Sato T, Beck F, van Oudenaarden A, Clevers H, Deschamps J . Transformation of intestinal stem cells into gastric stem cells on loss of transcription factor Cdx2 . Nature Communications . 5 . 1 . 5728 . December 2014 . 25500896 . 4284662 . 10.1038/ncomms6728 . free . 2014NatCo...5.5728S .
7. Stringer EJ, Duluc I, Saandi T, Davidson I, Bialecka M, Sato T, Barker N, Clevers H, Pritchard CA, Winton DJ, Wright NA, Freund JN, Deschamps J, Beck F . Cdx2 determines the fate of postnatal intestinal endoderm . Development . 139 . 3 . 465–474 . February 2012 . 22190642 . 3252350 . 10.1242/dev.070722 . free .
8. Beck F, Chawengsaksophak K, Waring P, Playford RJ, Furness JB . Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice . Proceedings of the National Academy of Sciences of the United States of America . 96 . 13 . 7318–7323 . June 1999 . 10377412 . 22083 . 10.1073/pnas.96.13.7318 . free . 1999PNAS...96.7318B .
9. Mutoh H, Hakamata Y, Sato K, Eda A, Yanaka I, Honda S, Osawa H, Kaneko Y, Sugano K . Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice . Biochemical and Biophysical Research Communications . 294 . 2 . 470–479 . June 2002 . 12051735 . 10.1016/s0006-291x(02)00480-1 .
10. Rawat VP, Cusan M, Deshpande A, Hiddemann W, Quintanilla-Martinez L, Humphries RK, Bohlander SK, Feuring-Buske M, Buske C . Ectopic expression of the homeobox gene Cdx2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia . Proceedings of the National Academy of Sciences of the United States of America . 101 . 3 . 817–822 . January 2004 . 14718672 . 321764 . 10.1073/pnas.0305555101 . free . 2004PNAS..101..817R .
11. Scholl C, Bansal D, Döhner K, Eiwen K, Huntly BJ, Lee BH, Rücker FG, Schlenk RF, Bullinger L, Döhner H, Gilliland DG, Fröhling S . The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis . The Journal of Clinical Investigation . 117 . 4 . 1037–1048 . April 2007 . 17347684 . 1810574 . 10.1172/JCI30182 .
12. Debruyne PR, Witek M, Gong L, Birbe R, Chervoneva I, Jin T, Domon-Cell C, Palazzo JP, Freund JN, Li P, Pitari GM, Schulz S, Waldman SA . Bile acids induce ectopic expression of intestinal guanylyl cyclase C Through nuclear factor-kappaB and Cdx2 in human esophageal cells . Gastroenterology . 130 . 4 . 1191–1206 . April 2006 . 16618413 . 10.1053/j.gastro.2005.12.032 . free .
13. Liu Q, Teh M, Ito K, Shah N, Ito Y, Yeoh KG . CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer . Modern Pathology . 20 . 12 . 1286–1297 . December 2007 . 17906616 . 10.1038/modpathol.3800968 . free .
14. Web site: Altered Nuclear Transfer as a Morally Acceptable Means for the Procurement of Human Embryonic Stem Cells . Hurlbut WB . 2004 . The President's Council on Bioethics . The White House of the United States of America . https://web.archive.org/web/20080517051256/http://www.bioethics.gov/background/hurlbut.html . May 17, 2008 . 2008-07-16 . dead .
15. Web site: The creepy solution to the stem-cell debate . Saletan W . William Saletan . December 6, 2004 . . August 3, 2024.
16. Hurlbut WB . Ethics and embryonic stem cell research: altered nuclear transfer as a way forward . BioDrugs . 21 . 2 . 79–83 . 2007 . 17402791 . 10.2165/00063030-200721020-00002 . 26102470 .
17. Hussain MA, Habener JF . Glucagon gene transcription activation mediated by synergistic interactions of pax-6 and cdx-2 with the p300 co-activator . The Journal of Biological Chemistry . 274 . 41 . 28950–28957 . October 1999 . 10506141 . 10.1074/jbc.274.41.28950 . free .