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Gene Review

CDX2  -  caudal type homeobox 2

Homo sapiens

Synonyms: CDX-3, CDX2/AS, CDX3, Caudal-type homeobox protein 2, Homeobox protein CDX-2
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Disease relevance of CDX2


Psychiatry related information on CDX2


High impact information on CDX2

  • The mammalian homeobox transcription factor CDX2 has key roles in intestinal development and differentiation [1].
  • CONCLUSIONS: Transformation associated with reflux at the gastroesophageal junction reflects activation by bile acid and acid of a transcriptional program involving NF-kappaB and Cdx2, which mediate intestinal metaplasia and ectopic expression of GC-C [9].
  • In turn, induction of Cdx2 expression by deoxycholate was mediated by binding sites in the proximal promoter for nuclear factor kappaB (NF-kappaB) [9].
  • Moreover, a dominant negative construct for NF-kappaB prevented deoxycholate-induced p50 nuclear translocation and activation of the Cdx2 promoter [9].
  • METHODS: HT-29 and WiDr colorectal cancer (CRC) cells with low endogenous CDX2 expression were transduced with a CDX2 expression vector, and gene expression changes were assessed by microarrays [10].

Chemical compound and disease context of CDX2


Biological context of CDX2

  • Finally, in colon epithelium-derived cells, SOX9 transcriptionally represses the CDX2 and MUC2 genes, normally expressed in the mature villus cells of the intestinal epithelium, and may therefore contribute to the Wnt-dependent maintenance of a progenitor cell phenotype [15].
  • The CDX2 homeobox transcription factor plays key roles in intestinal development and homeostasis [16].
  • Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression [17].
  • In differentiated Caco-2 cells, the ACAT2 expression significantly decreases when the endogenous CDX2 or HNF1alpha expression is suppressed by using RNAi (RNA interference) technology [18].
  • First, a direct in-frame fusion between exon 2 of ETV6 and exon 2 of CDX2, and second, a transcript that had an additional sequence of unknown origin spliced between these same exons [19].

Anatomical context of CDX2


Associations of CDX2 with chemical compounds

  • We propose a novel role for APC and CDX2 in controlling retinoic acid biosynthesis and in promoting a retinoid-induced program of colonocyte differentiation [22].
  • EMSA revealed that CDX2 bound to the MUC2 gene cis element, MUC2-WT [17].
  • 4) Treatment of Caco-2/15 cells with MG132 (a proteasome inhibitor) and (R)-roscovitine (a specific Cdk2 inhibitor) induced an increase in CDX2 protein levels [23].
  • 3) Cdk2 interacted with CDX2 and phosphorylated CDX2, as determined by pull-down glutathione S-transferase and immunoprecipitation experiments with proliferating undifferentiated Caco-2/15 cell extracts [23].
  • Our aim was to evaluate the immunohistochemical expression of CDX2 in normal tissues and in 184 formalin-fixed and paraffin-embedded ETs to verify whether it could be used to identify intestinal ETs with a high degree of sensitivity and specificity [24].

Co-localisations of CDX2


Physical interactions of CDX2

  • CDX2 binds to the IGFBP-3 gene promoter and can repress IGFBP-3 transcription, protein expression and secretion [26].

Regulatory relationships of CDX2

  • We show that wild-type CDX2 activates the GKLF promoter and that the mutated CDX2 has a dominant negative effect on wild-type function [27].
  • It is noteworthy that CDX2 was expressed in the antral and fundic mucosa in the absence of the expression of CDX1 and gene markers for intestinal metaplasia [11].
  • Expression of CDX2 was found to be induced by restoring expression of wild type APC in a colorectal cancer cell line [28].
  • CDX2 is known to regulate class I homeobox genes and its expression in hematopoietic cells may critically alter the balance between differentiation and proliferation [19].
  • In addition, Cdx2 was shown to cooperate with HNF1alpha to synergistically activate the UGT1A8, -1A9, and -1A10 promoters [29].
  • The Cdx2 promoter was activated by T-cell factor 4 (TCF4) -independent activated beta-catenin, as well as Cdx2 itself, through the region from -39 to +9 bp relative to transcription start site [30].

Other interactions of CDX2

  • SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes [15].
  • The caudal-type homeodomain transcription factors 1 (CDX1) and 2 (CDX2) regulate axial development and intestinal differentiation [2].
  • The incidence of expression of CDX2 and TFF1 was maximal in IPNL type 3 [31].
  • These data suggest that p21 is a transcriptional target of CDX2 [16].
  • These were mostly graded as carcinoma in situ (94%); they rarely expressed CDX2 (6%) or MUC2 (19%) but often showed MUC1 labeling (44%) [32].

Analytical, diagnostic and therapeutic context of CDX2


  1. Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice. Aoki, K., Tamai, Y., Horiike, S., Oshima, M., Taketo, M.M. Nat. Genet. (2003) [Pubmed]
  2. Expression of the caudal-type homeodomain transcription factors CDX 1/2 and outcome in carcinomas of the ampulla of Vater. Hansel, D.E., Maitra, A., Lin, J.W., Goggins, M., Argani, P., Yeo, C.J., Piantadosi, S., Leach, S.D., Biankin, A.V. J. Clin. Oncol. (2005) [Pubmed]
  3. PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas. Sakai, H., Eishi, Y., Li, X.L., Akiyama, Y., Miyake, S., Takizawa, T., Konishi, N., Tatematsu, M., Koike, M., Yuasa, Y. Gut (2004) [Pubmed]
  4. Expression of CDX2 in normal and neoplastic human colon tissue and during differentiation of an in vitro model system. Qualtrough, D., Hinoi, T., Fearon, E., Paraskeva, C. Gut (2002) [Pubmed]
  5. Primary mucinous (so-called colloid) carcinomas of the lung: a clinicopathologic and immunohistochemical study with special reference to CDX-2 homeobox gene and MUC2 expression. Rossi, G., Murer, B., Cavazza, A., Losi, L., Natali, P., Marchioni, A., Migaldi, M., Capitanio, G., Brambilla, E. Am. J. Surg. Pathol. (2004) [Pubmed]
  6. Relationship of CDX2 loss with molecular features and prognosis in colorectal cancer. Baba, Y., Nosho, K., Shima, K., Freed, E., Irahara, N., Philips, J., Meyerhardt, J.A., Hornick, J.L., Shivdasani, R.A., Fuchs, C.S., Ogino, S. Clin. Cancer Res. (2009) [Pubmed]
  7. Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients. Yuasa, Y., Nagasaki, H., Akiyama, Y., Sakai, H., Nakajima, T., Ohkura, Y., Takizawa, T., Koike, M., Tani, M., Iwai, T., Sugihara, K., Imai, K., Nakachi, K. Carcinogenesis (2005) [Pubmed]
  8. The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Uitterlinden, A.G., Ralston, S.H., Brandi, M.L., Carey, A.H., Grinberg, D., Langdahl, B.L., Lips, P., Lorenc, R., Obermayer-Pietsch, B., Reeve, J., Reid, D.M., Amidei, A., Bassiti, A., Bustamante, M., Husted, L.B., Diez-Perez, A., Dobnig, H., Dunning, A.M., Enjuanes, A., Fahrleitner-Pammer, A., Fang, Y., Karczmarewicz, E., Kruk, M., van Leeuwen, J.P., Mavilia, C., van Meurs, J.B., Mangion, J., McGuigan, F.E., Pols, H.A., Renner, W., Rivadeneira, F., van Schoor, N.M., Scollen, S., Sherlock, R.E., Ioannidis, J.P. Ann. Intern. Med. (2006) [Pubmed]
  9. Bile acids induce ectopic expression of intestinal guanylyl cyclase C Through nuclear factor-kappaB and Cdx2 in human esophageal cells. Debruyne, P.R., Witek, M., Gong, L., Birbe, R., Chervoneva, I., Jin, T., Domon-Cell, C., Palazzo, J.P., Freund, J.N., Li, P., Pitari, G.M., Schulz, S., Waldman, S.A. Gastroenterology (2006) [Pubmed]
  10. CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium. Hinoi, T., Gesina, G., Akyol, A., Kuick, R., Hanash, S., Giordano, T.J., Gruber, S.B., Fearon, E.R. Gastroenterology (2005) [Pubmed]
  11. Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia. Eda, A., Osawa, H., Yanaka, I., Satoh, K., Mutoh, H., Kihira, K., Sugano, K. J. Gastroenterol. (2002) [Pubmed]
  12. Value of CDX2, villin, and alpha-methylacyl coenzyme A racemase immunostains in the distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma. Suh, N., Yang, X.J., Tretiakova, M.S., Humphrey, P.A., Wang, H.L. Mod. Pathol. (2005) [Pubmed]
  13. Expression of the intestinal transcription factor CDX2 in carcinoid tumors is a marker of midgut origin. Jaffee, I.M., Rahmani, M., Singhal, M.G., Younes, M. Arch. Pathol. Lab. Med. (2006) [Pubmed]
  14. A close relationship between intestinal metaplasia and Cdx2 expression in human gallbladders with cholelithiasis. Sakamoto, H., Mutoh, H., Ido, K., Satoh, K., Hayakawa, H., Sugano, K. Hum. Pathol. (2007) [Pubmed]
  15. SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. Blache, P., van de Wetering, M., Duluc, I., Domon, C., Berta, P., Freund, J.N., Clevers, H., Jay, P. J. Cell Biol. (2004) [Pubmed]
  16. CDX2, a homeobox transcription factor, upregulates transcription of the p21/WAF1/CIP1 gene. Bai, Y.Q., Miyake, S., Iwai, T., Yuasa, Y. Oncogene (2003) [Pubmed]
  17. Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression. Yamamoto, H., Bai, Y.Q., Yuasa, Y. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  18. Human acyl-CoA:cholesterol acyltransferase 2 gene expression in intestinal Caco-2 cells and in hepatocellular carcinoma. Song, B.L., Wang, C.H., Yao, X.M., Yang, L., Zhang, W.J., Wang, Z.Z., Zhao, X.N., Yang, J.B., Qi, W., Yang, X.Y., Inoue, K., Lin, Z.X., Zhang, H.Z., Kodama, T., Chang, C.C., Liu, Y.K., Chang, T.Y., Li, B.L. Biochem. J. (2006) [Pubmed]
  19. Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Chase, A., Reiter, A., Burci, L., Cazzaniga, G., Biondi, A., Pickard, J., Roberts, I.A., Goldman, J.M., Cross, N.C. Blood (1999) [Pubmed]
  20. Expression of homeodomain protein CDX2 in gallbladder carcinomas. Wu, X.S., Akiyama, Y., Igari, T., Kawamura, T., Hiranuma, S., Shibata, T., Tsuruta, K., Koike, M., Arii, S., Yuasa, Y. J. Cancer Res. Clin. Oncol. (2005) [Pubmed]
  21. Increased CDX2 and decreased PITX1 homeobox gene expression in Barrett's esophagus and Barrett's-associated adenocarcinoma. Lord, R.V., Brabender, J., Wickramasinghe, K., DeMeester, S.R., Holscher, A., Schneider, P.M., Danenberg, P.V., DeMeester, T.R. Surgery (2005) [Pubmed]
  22. The tumor suppressor adenomatous polyposis coli and caudal related homeodomain protein regulate expression of retinol dehydrogenase L. Jette, C., Peterson, P.W., Sandoval, I.T., Manos, E.J., Hadley, E., Ireland, C.M., Jones, D.A. J. Biol. Chem. (2004) [Pubmed]
  23. Cdk2-dependent phosphorylation of homeobox transcription factor CDX2 regulates its nuclear translocation and proteasome-mediated degradation in human intestinal epithelial cells. Boulanger, J., Vézina, A., Mongrain, S., Boudreau, F., Perreault, N., Auclair, B.A., Lainé, J., Asselin, C., Rivard, N. J. Biol. Chem. (2005) [Pubmed]
  24. CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors. La Rosa, S., Rigoli, E., Uccella, S., Chiaravalli, A.M., Capella, C. Virchows Arch. (2004) [Pubmed]
  25. CDX2 co-localizes with liver-intestine cadherin in intestinal metaplasia and adenocarcinoma of the stomach. Ko, S., Chu, K.M., Luk, J.M., Wong, B.W., Yuen, S.T., Leung, S.Y., Wong, J. J. Pathol. (2005) [Pubmed]
  26. CDX2 promotes anchorage-independent growth by transcriptional repression of IGFBP-3. Chun, S.Y., Chen, F., Washburn, J.G., MacDonald, J.W., Innes, K.L., Zhao, R., Cruz-Correa, M.R., Dang, L.H., Dang, D.T. Oncogene (2007) [Pubmed]
  27. Expression of the gut-enriched Krüppel-like factor (Krüppel-like factor 4) gene in the human colon cancer cell line RKO is dependent on CDX2. Dang, D.T., Mahatan, C.S., Dang, L.H., Agboola, I.A., Yang, V.W. Oncogene (2001) [Pubmed]
  28. CDX2 is mutated in a colorectal cancer with normal APC/beta-catenin signaling. da Costa, L.T., He, T.C., Yu, J., Sparks, A.B., Morin, P.J., Polyak, K., Laken, S., Vogelstein, B., Kinzler, K.W. Oncogene (1999) [Pubmed]
  29. Coordinate regulation of the human UDP-glucuronosyltransferase 1A8, 1A9, and 1A10 genes by hepatocyte nuclear factor 1alpha and the caudal-related homeodomain protein 2. Gregory, P.A., Lewinsky, R.H., Gardner-Stephen, D.A., Mackenzie, P.I. Mol. Pharmacol. (2004) [Pubmed]
  30. A functional role of Cdx2 in beta-catenin signaling during transdifferentiation in endometrial carcinomas. Saegusa, M., Hashimura, M., Kuwata, T., Hamano, M., Wani, Y., Okayasu, I. Carcinogenesis (2007) [Pubmed]
  31. Characterization of intrahepatic cholangiocarcinoma of the intraductal growth-type and its precursor lesions. Yeh, T.S., Tseng, J.H., Chen, T.C., Liu, N.J., Chiu, C.T., Jan, Y.Y., Chen, M.F. Hepatology (2005) [Pubmed]
  32. Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an "intestinal" pathway of carcinogenesis in the pancreas. Adsay, N.V., Merati, K., Basturk, O., Iacobuzio-Donahue, C., Levi, E., Cheng, J.D., Sarkar, F.H., Hruban, R.H., Klimstra, D.S. Am. J. Surg. Pathol. (2004) [Pubmed]
  33. Aberrant expression of CDX2 is closely related to the intestinal metaplasia and MUC2 expression in intraductal papillary neoplasm of the liver in hepatolithiasis. Ishikawa, A., Sasaki, M., Ohira, S., Ohta, T., Oda, K., Nimura, Y., Chen, M.F., Jan, Y.Y., Yeh, T.S., Nakanuma, Y. Lab. Invest. (2004) [Pubmed]
  34. Ectopic expression of the homeobox gene Cdx2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia. Rawat, V.P., Cusan, M., Deshpande, A., Hiddemann, W., Quintanilla-Martinez, L., Humphries, R.K., Bohlander, S.K., Feuring-Buske, M., Buske, C. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  35. Identifying colorectal metastases in liver biopsies: the novel CDX2 antibody is less specific than the cytokeratin 20+/7- phenotype. Tot, T. Med. Sci. Monit. (2004) [Pubmed]
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