Homeobox protein CDX-2

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,^[5][6] 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.^[7] Together with CDX1 and CDX4, CDX2 is one of three caudal-related genes in the human genome.

CDX2
Identifiers
Aliases	CDX2, CDX-3, CDX2/AS, CDX3, caudal type homeobox 2, Cdx2
External IDs	OMIM: 600297; MGI: 88361; HomoloGene: 968; GeneCards: CDX2; OMA:CDX2 - orthologs
Gene location (Human) Chr. Chromosome 13 (human)[1] Band 13q12.2 Start 27,960,918 bp[1] End 27,969,315 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 G3|5 86.86 cM Start 147,237,615 bp[2] End 147,244,080 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of transverse colon rectum duodenum epithelium of colon mucosa of ileum mucosa of sigmoid colon appendix jejunal mucosa body of pancreas islet of Langerhans Top expressed in Paneth cell tail of embryo crypt of lieberkuhn of small intestine primitive streak migratory enteric neural crest cell ileum jejunum duodenum Epithelium of large intestine left colon More reference expression data BioGPS More reference expression data
Gene ontology Molecular function RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA binding sequence-specific DNA binding transcription corepressor activity DNA-binding transcription factor activity DNA-binding transcription repressor activity, RNA polymerase II-specific double-stranded DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific methyl-CpG binding RNA polymerase II transcription regulatory region sequence-specific DNA binding Cellular component transcription repressor complex nucleoplasm condensed nuclear chromosome nucleus protein-containing complex Biological process pattern specification process cell differentiation regulation of transcription, DNA-templated regulation of somitogenesis somatic stem cell population maintenance endosome to lysosome transport placenta development regulation of transcription by RNA polymerase II labyrinthine layer development negative regulation of transcription by RNA polymerase II transcription by RNA polymerase II transcription, DNA-templated positive regulation of transcription, DNA-templated multicellular organism development blood vessel development trophectodermal cell differentiation establishment or maintenance of epithelial cell apical/basal polarity positive regulation of cell differentiation intestinal epithelial cell differentiation positive regulation of cell population proliferation animal organ morphogenesis anterior/posterior axis specification blastocyst development anterior/posterior pattern specification Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1045 12591 Ensembl ENSG00000165556 ENSMUSG00000029646 UniProt Q99626 P43241 RefSeq (mRNA) NM_001265 NM_001354700 NM_007673 RefSeq (protein) NP_001256 NP_001341629 NP_031699 Location (UCSC) Chr 13: 27.96 – 27.97 Mb Chr 5: 147.24 – 147.24 Mb PubMed search [3] [4]
Wikidata
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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.^[6] 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.^[8][9] CDX2 is also required for the development of the placenta.^[9]

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,^[10][11] 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.^[12] Conversely, the over-expression of CDX2 leads to the formation of intestinal epithelium in the stomach.^[13]

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.^[9]

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.^[14][15] 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.^[16]

Biomarker for intestinal cancer

CDX2 is also used in diagnostic surgical pathology as a marker for gastrointestinal differentiation, especially colorectal.^[17]

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.^[18] 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.^[19] Other genes that have been proposed for this purpose include Hnf4, which is required for gastrulation.^[18][20]

Interactions

CDX2 has been shown to interact with EP300,^[21] and PAX6.^[21]

References

1. GRCh38: Ensembl release 89: ENSG00000165556 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029646 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. German MS, Wang J, Fernald AA, Espinosa R, Le Beau MM, Bell GI (November 1994). "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. doi:10.1006/geno.1994.1639. PMID 7698771.
6. Beck F, Erler T, Russell A, James R (November 1995). "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. doi:10.1002/aja.1002040302. PMID 8573715. S2CID 19576530.
7. Brooke NM, Garcia-Fernàndez J, Holland PW (April 1998). "The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster". Nature. 392 (6679): 920–922. Bibcode:1998Natur.392..920B. doi:10.1038/31933. PMID 9582071. S2CID 4398740.
8. Chawengsaksophak K, James R, Hammond VE, Köntgen F, Beck F (March 1997). "Homeosis and intestinal tumours in Cdx2 mutant mice". Nature. 386 (6620): 84–87. Bibcode:1997Natur.386...84C. doi:10.1038/386084a0. PMID 9052785. S2CID 4252265.
9. Chawengsaksophak K, de Graaff W, Rossant J, Deschamps J, Beck F (May 2004). "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. Bibcode:2004PNAS..101.7641C. doi:10.1073/pnas.0401654101. PMC 419659. PMID 15136723.
10. Simmini S, Bialecka M, Huch M, Kester L, van de Wetering M, Sato T, Beck F, van Oudenaarden A, Clevers H, Deschamps J (December 2014). "Transformation of intestinal stem cells into gastric stem cells on loss of transcription factor Cdx2". Nature Communications. 5 (1): 5728. Bibcode:2014NatCo...5.5728S. doi:10.1038/ncomms6728. PMC 4284662. PMID 25500896.
11. 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 (February 2012). "Cdx2 determines the fate of postnatal intestinal endoderm". Development. 139 (3): 465–474. doi:10.1242/dev.070722. PMC 3252350. PMID 22190642.
12. Beck F, Chawengsaksophak K, Waring P, Playford RJ, Furness JB (June 1999). "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. Bibcode:1999PNAS...96.7318B. doi:10.1073/pnas.96.13.7318. PMC 22083. PMID 10377412.
13. Mutoh H, Hakamata Y, Sato K, Eda A, Yanaka I, Honda S, Osawa H, Kaneko Y, Sugano K (June 2002). "Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice". Biochemical and Biophysical Research Communications. 294 (2): 470–479. doi:10.1016/s0006-291x(02)00480-1. PMID 12051735.
14. Rawat VP, Cusan M, Deshpande A, Hiddemann W, Quintanilla-Martinez L, Humphries RK, Bohlander SK, Feuring-Buske M, Buske C (January 2004). "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. Bibcode:2004PNAS..101..817R. doi:10.1073/pnas.0305555101. PMC 321764. PMID 14718672.
15. Scholl C, Bansal D, Döhner K, Eiwen K, Huntly BJ, Lee BH, Rücker FG, Schlenk RF, Bullinger L, Döhner H, Gilliland DG, Fröhling S (April 2007). "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. doi:10.1172/JCI30182. PMC 1810574. PMID 17347684.
16. 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 (April 2006). "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. doi:10.1053/j.gastro.2005.12.032. PMID 16618413.
17. Liu Q, Teh M, Ito K, Shah N, Ito Y, Yeoh KG (December 2007). "CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer". Modern Pathology. 20 (12): 1286–1297. doi:10.1038/modpathol.3800968. PMID 17906616.
18. Hurlbut WB (2004). "Altered Nuclear Transfer as a Morally Acceptable Means for the Procurement of Human Embryonic Stem Cells". The President's Council on Bioethics. The White House of the United States of America. Archived from the original on May 17, 2008. Retrieved 2008-07-16.
19. Saletan W (December 6, 2004). "The creepy solution to the stem-cell debate". Slate. Retrieved August 3, 2024.
20. Hurlbut WB (2007). "Ethics and embryonic stem cell research: altered nuclear transfer as a way forward". BioDrugs. 21 (2): 79–83. doi:10.2165/00063030-200721020-00002. PMID 17402791. S2CID 26102470.
21. Hussain MA, Habener JF (October 1999). "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. doi:10.1074/jbc.274.41.28950. PMID 10506141.

Further reading

• Suh E, Chen L, Taylor J, Traber PG (November 1994). "A homeodomain protein related to caudal regulates intestine-specific gene transcription". Molecular and Cellular Biology. 14 (11): 7340–7351. doi:10.1128/mcb.14.11.7340. PMC 359269. PMID 7935448.
• Inoue H, Riggs AC, Tanizawa Y, Ueda K, Kuwano A, Liu L, Donis-Keller H, Permutt MA (June 1996). "Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene". Diabetes. 45 (6): 789–794. doi:10.2337/diabetes.45.6.789. PMID 8635654.
• Mallo GV, Rechreche H, Frigerio JM, Rocha D, Zweibaum A, Lacasa M, Jordan BR, Dusetti NJ, Dagorn JC, Iovanna JL (February 1997). "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. doi:10.1002/(SICI)1097-0215(19970220)74:1<35::AID-IJC7>3.0.CO;2-1. PMID 9036867. S2CID 46416077.
• Chawengsaksophak K, James R, Hammond VE, Köntgen F, Beck F (March 1997). "Homeosis and intestinal tumours in Cdx2 mutant mice". Nature. 386 (6620): 84–87. Bibcode:1997Natur.386...84C. doi:10.1038/386084a0. PMID 9052785. S2CID 4252265.
• Walters JR, Howard A, Rumble HE, Prathalingam SR, Shaw-Smith CJ, Legon S (August 1997). "Differences in expression of homeobox transcription factors in proximal and distal human small intestine". Gastroenterology. 113 (2): 472–477. doi:10.1053/gast.1997.v113.pm9247466. PMID 9247466.
• Drummond F, Putt W, Fox M, Edwards YH (September 1997). "Cloning and chromosome assignment of the human CDX2 gene". Annals of Human Genetics. 61 (Pt 5): 393–400. doi:10.1046/j.1469-1809.1997.6150393.x. PMID 9459001. S2CID 45461007.
• Yamamoto H, Miyamoto K, Li B, Taketani Y, Kitano M, Inoue Y, Morita K, Pike JW, Takeda E (February 1999). "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. doi:10.1359/jbmr.1999.14.2.240. PMID 9933478. S2CID 45176819.
• Hussain MA, Habener JF (October 1999). "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. doi:10.1074/jbc.274.41.28950. PMID 10506141.
• Mitchelmore C, Troelsen JT, Spodsberg N, Sjöström H, Norén O (March 2000). "Interaction between the homeodomain proteins Cdx2 and HNF1alpha mediates expression of the lactase-phlorizin hydrolase gene". The Biochemical Journal. 346 (Pt 2): 529–535. doi:10.1042/0264-6021:3460529. PMC 1220882. PMID 10677375.
• Sivagnanasundaram S, Islam I, Talbot I, Drummond F, Walters JR, Edwards YH (January 2001). "The homeobox gene CDX2 in colorectal carcinoma: a genetic analysis". British Journal of Cancer. 84 (2): 218–225. doi:10.1054/bjoc.2000.1544. PMC 2363702. PMID 11161380.
• Rings EH, Boudreau F, Taylor JK, Moffett J, Suh ER, Traber PG (December 2001). "Phosphorylation of the serine 60 residue within the Cdx2 activation domain mediates its transactivation capacity". Gastroenterology. 121 (6): 1437–1450. doi:10.1053/gast.2001.29618. PMID 11729123.
• Hinoi T, Tani M, Lucas PC, Caca K, Dunn RL, Macri E, Loda M, Appelman HD, Cho KR, Fearon ER (December 2001). "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. doi:10.1016/S0002-9440(10)63074-X. PMC 1850596. PMID 11733373.
• Mizoshita T, Inada K, Tsukamoto T, Kodera Y, Yamamura Y, Hirai T, Kato T, Joh T, Itoh M, Tatematsu M (2002). "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. doi:10.1007/PL00011741. PMID 11846061.
• Eda A, Osawa H, Yanaka I, Satoh K, Mutoh H, Kihira K, Sugano K (2002). "Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia". Journal of Gastroenterology. 37 (2): 94–100. doi:10.1007/s005350200002. PMID 11871772. S2CID 20514893.
• Qualtrough D, Hinoi T, Fearon E, Paraskeva C (August 2002). "Expression of CDX2 in normal and neoplastic human colon tissue and during differentiation of an in vitro model system". Gut. 51 (2): 184–190. doi:10.1136/gut.51.2.184. PMC 1773308. PMID 12117877.
• Moucadel V, Totaro MS, Dell CD, Soubeyran P, Dagorn JC, Freund JN, Iovanna JL (September 2002). "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. doi:10.1016/S0006-291X(02)02250-7. PMID 12270138.
• Song BL, Qi W, Wang CH, Yang JB, Yang XY, Lin ZX, Li BL (January 2003). "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. PMID 12518221.

External links

• CDX2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human CDX2 genome location and CDX2 gene details page in the UCSC Genome Browser.