Homeobox protein CDX-2
Homeobox protein CDX-2is aproteinthat in humans is encoded by theCDX2gene.The CDX-2 protein is ahomeoboxtranscription factorexpressed in the nuclei of intestinalepithelial cells,[5][6]playing an essential role in the development and function of thedigestive system.CDX2is part of theParaHoxgene cluster, a group of three highly conserved developmental genes present in mostvertebratespecies.[7]Together withCDX1andCDX4,CDX2is one of threecaudal-related genes in the human genome.
Function
[edit]In common with the two other Cdx genes, CDX2 regulates several essential processes in the development and function of the lowergastrointestinal tract(from the duodenum to the anus) in vertebrates. In vertebrateembryonic development,CDX2 becomes active inendodermal cellsthat are posterior to the developing stomach.[6]These cells eventually form the intestinalepithelium.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 theplacenta.[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 thetrophectodermlineage of cells in theblastocystof mouse and human. Trophectoderm cells contribute to theplacenta.[9]
Pathology
[edit]Ectopic expression of CDX2 was reported in more than 85% of the human patients withacute 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 ofBarrett's esophaguswhere it has been shown that components from gastroesophageal reflux such asbile acidsare able to induce the expression of an intestinal differentiation program through up-regulation of NF-κB and CDX2.[16]
Biomarker for intestinal cancer
[edit]CDX2 is also used in diagnostic surgical pathology as a marker for gastrointestinal differentiation, especially colorectal.[17]
Possible use in stem cell research
[edit]This gene (or, more specifically, the equivalent gene in humans) has come up in the proposal by thePresident's Council on Bioethics,as a solution to thestem cellcontroversy.[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 includeHnf4,which is required forgastrulation.[18][20]
Interactions
[edit]CDX2 has been shown tointeractwithEP300,[21]andPAX6.[21]
References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000165556–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000029646–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^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.PMID7698771.
- ^abBeck 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.PMID8573715.S2CID19576530.
- ^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.PMID9582071.S2CID4398740.
- ^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.PMID9052785.S2CID4252265.
- ^abcChawengsaksophak 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.PMC419659.PMID15136723.
- ^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.PMC4284662.PMID25500896.
- ^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.PMC3252350.PMID22190642.
- ^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.PMC22083.PMID10377412.
- ^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.PMID12051735.
- ^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.PMC321764.PMID14718672.
- ^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.PMC1810574.PMID17347684.
- ^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.PMID16618413.
- ^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.PMID17906616.
- ^abHurlbut 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 fromthe originalon May 17, 2008.Retrieved2008-07-16.
- ^Saletan W(December 6, 2004)."The creepy solution to the stem-cell debate".Slate.RetrievedAugust 3,2024.
- ^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.PMID17402791.S2CID26102470.
- ^abHussain 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.PMID10506141.
Further reading
[edit]- 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.PMC359269.PMID7935448.
- 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.PMID8635654.
- 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.PMID9036867.S2CID46416077.
- 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.PMID9052785.S2CID4252265.
- 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.PMID9247466.
- 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.PMID9459001.S2CID45461007.
- 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.PMID9933478.S2CID45176819.
- 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.PMID10506141.
- Mitchelmore C, Troelsen JT, Spodsberg N, Sjöström H, Norén O (March 2000)."Interaction between the homeodomain proteins Cdx2 and HNF1 Alpha mediates expression of the lactase-phlorizin hydrolase gene".The Biochemical Journal.346(Pt 2): 529–535.doi:10.1042/0264-6021:3460529.PMC1220882.PMID10677375.
- 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.PMC2363702.PMID11161380.
- 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.PMID11729123.
- 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.PMC1850596.PMID11733373.
- 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.PMID11846061.
- 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.PMID11871772.S2CID20514893.
- 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.PMC1773308.PMID12117877.
- 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.PMID12270138.
- 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.PMID12518221.
External links
[edit]- CDX2+protein,+humanat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- HumanCDX2genome location andCDX2gene details page in theUCSC Genome Browser.