Biology:CDX2

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Homeobox protein CDX-2 is a protein that in humans is encoded by the CDX2 gene. The CDX2 protein is a homeobox transcription factor expressed in the nuclei of intestinal epithelial cells,[1][2] 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.[3] 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.[2] 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.[5]

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.[5]

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]

References

  1. ↑ "Localization of the genes encoding two transcription factors, LMX1 and CDX3, regulating insulin gene expression to human chromosomes 1 and 13". Genomics 24 (2): 403–4. Nov 1994. doi:10.1006/geno.1994.1639. PMID 7698771. 
  2. ↑ 2.0 2.1 Beck, F.; Erler, T.; Russell, A.; James, R. (1995). "Expression of Cdx-2 in the mouse embryo and placenta: Possible role in patterning of the extra-embryonic membranes" (in en). Developmental Dynamics 204 (3): 219–227. doi:10.1002/aja.1002040302. PMID 8573715. 
  3. ↑ Brooke, Nina M.; Garcia-Fernàndez, Jordi; Holland, Peter W. H. (1998). "The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster". Nature 392 (6679): 920–922. doi:10.1038/31933. ISSN 0028-0836. PMID 9582071. Bibcode: 1998Natur.392..920B. http://dx.doi.org/10.1038/31933. 
  4. ↑ Chawengsaksophak, K.; James, R.; Hammond, V. E.; Köntgen, F.; Beck, F. (1997). "Homeosis and intestinal tumours in Cdx2 mutant mice" (in en). Nature 386 (6620): 84–87. doi:10.1038/386084a0. ISSN 1476-4687. PMID 9052785. Bibcode: 1997Natur.386...84C. https://www.nature.com/articles/386084a0. 
  5. ↑ 5.0 5.1 5.2 "Cdx2 is essential for axial elongation in mouse development". Proceedings of the National Academy of Sciences of the United States of America 101 (20): 7641–5. May 2004. doi:10.1073/pnas.0401654101. PMID 15136723. Bibcode: 2004PNAS..101.7641C. 
  6. ↑ Simmini, Salvatore; Bialecka, Monika; Huch, Meritxell; Kester, Lennart; van de Wetering, Marc; Sato, Toshiro; Beck, Felix; van Oudenaarden, Alexander et al. (2014-12-11). "Transformation of intestinal stem cells into gastric stem cells on loss of transcription factor Cdx2" (in en). Nature Communications 5 (1): 5728. doi:10.1038/ncomms6728. ISSN 2041-1723. PMID 25500896. Bibcode: 2014NatCo...5.5728S. 
  7. ↑ Stringer, Emma J.; Duluc, Isabelle; Saandi, Thoueiba; Davidson, Irwin; Bialecka, Monika; Sato, Toshiro; Barker, Nick; Clevers, Hans et al. (2012-02-01). "Cdx2 determines the fate of postnatal intestinal endoderm" (in en). Development 139 (3): 465–474. doi:10.1242/dev.070722. ISSN 0950-1991. PMID 22190642. 
  8. ↑ Beck, Felix; Chawengsaksophak, Kallayanee; Waring, Paul; Playford, Raymond J.; Furness, John B. (1999-06-22). "Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice" (in en). Proceedings of the National Academy of Sciences 96 (13): 7318–7323. doi:10.1073/pnas.96.13.7318. ISSN 0027-8424. PMID 10377412. Bibcode: 1999PNAS...96.7318B. 
  9. ↑ Mutoh, Hiroyuki; Hakamata, Yoji; Sato, Kiichi; Eda, Akashi; Yanaka, Ichiro; Honda, Sayaka; Osawa, Hiroyuki; Kaneko, Yoshinari et al. (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. ISSN 0006-291X. PMID 12051735. http://dx.doi.org/10.1016/s0006-291x(02)00480-1. 
  10. ↑ "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): 817–22. Jan 2004. doi:10.1073/pnas.0305555101. PMID 14718672. Bibcode: 2004PNAS..101..817R. 
  11. ↑ "The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis". The Journal of Clinical Investigation 117 (4): 1037–48. Apr 2007. doi:10.1172/JCI30182. PMID 17347684. 
  12. ↑ "Bile acids induce ectopic expression of intestinal guanylyl cyclase C Through nuclear factor-kappaB and Cdx2 in human esophageal cells". Gastroenterology 130 (4): 1191–206. Apr 2006. doi:10.1053/j.gastro.2005.12.032. PMID 16618413. 
  13. ↑ "CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer". Modern Pathology 20 (12): 1286–97. Dec 2007. doi:10.1038/modpathol.3800968. PMID 17906616. 
  14. ↑ 14.0 14.1 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. http://www.bioethics.gov/background/hurlbut.html. 
  15. ↑ Saletan, William (2004-12-06). "The creepy solution to the stem-cell debate". http://slate.msn.com/id/2110670/fr/rss/. 
  16. ↑ "Ethics and embryonic stem cell research: altered nuclear transfer as a way forward". BioDrugs 21 (2): 79–83. 2007. doi:10.2165/00063030-200721020-00002. PMID 17402791. 
  17. ↑ 17.0 17.1 "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): 28950–7. Oct 1999. doi:10.1074/jbc.274.41.28950. PMID 10506141. 

Further reading

External links



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