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The Parahox gene Pdx1 is required to maintain positional identity in the adult foregut.
Holland AM, Garcia S, Naselli G, Macdonald RJ, Harrison LC
(2013) Int J Dev Biol 57: 391-8
MeSH Terms: Animals, CDX2 Transcription Factor, Digestive System Abnormalities, Duodenum, Female, Gastric Mucosa, Gastrointestinal Tract, Hamartoma, Homeodomain Proteins, Immunohistochemistry, Male, Mice, Mice, Knockout, Mice, Transgenic, Microscopy, Fluorescence, Stomach, Time Factors, Trans-Activators, Transcription Factors
Show Abstract · Added November 6, 2013
The homeobox gene Pdx1 is a key regulator of pancreas and foregut development. Loss of Pdx1 expression results in pancreas agenesis and impaired development of the gastro-duodenal domain including Brunner’s glands. We previously demonstrated a key role for Pdx1 in maintaining the integrity and function of insulin-secreting beta cells in the adult pancreas. In the present study, we aimed to determine if expression of Pdx1 is required to maintain the cellular identity of the gastro-duodenal domain in adult mice. Immunohistological studies were performed in a mouse model in which expression of Pdx1 was conditionally repressed with the doxycycline-responsive tetracycline transactivator system. Mice in which Pdx1 was chronically repressed developed hamartomas in the gastro-duodenal domain. These lesions appeared to arise from ectopic foci of anteriorized cells, consistent with a localised anterior homeotic shift. They emerge with the intercalation of tissue between the anteriorized and normal domains and appear strikingly similar to lesions in the colon of mice heterozygous for another Parahox gene, Cdx2. Continuing expression of Pdx1 into adult life is required to maintain regional cellular identity in the adult foregut, specifically at the gastro-duodenal boundary. Loss of Pdx1 expression leads to anterior transformation and intercalary regeneration of ectopic tissue. We propose a model in which the posterior dominance of classical Hox genes is mirrored by the Parahox genes, providing further evidence of the functional conservation of the Parahox genes. These findings may have implications for further understanding the molecular basis of gastro-duodenal metaplasia and gastro-intestinal transformations such as Barrett’s esophagus.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Caudal homeobox protein Cdx-2 cooperates with Wnt pathway to regulate claudin-1 expression in colon cancer cells.
Bhat AA, Sharma A, Pope J, Krishnan M, Washington MK, Singh AB, Dhawan P
(2012) PLoS One 7: e37174
MeSH Terms: Base Sequence, Binding Sites, CDX2 Transcription Factor, Cell Line, Tumor, Claudin-1, Colorectal Neoplasms, DNA, GATA4 Transcription Factor, Gene Expression Regulation, Homeodomain Proteins, Humans, Molecular Sequence Data, Promoter Regions, Genetic, Transcription, Genetic, Wnt Proteins
Show Abstract · Added June 28, 2013
Dysregulation of tight junctions (TJs) is often associated with human diseases including carcinogenesis and recent studies support role of TJ integral proteins in the regulation of Epithelial-to-Mesenchymal Transition (EMT). In this regard, expression of claudin-1, a key constituent of TJs, is highly increased in colon cancer and is causally associated with the tumor growth and progression. However, mechanism/s underlying regulation of claudin-1 expression in intestinal epithelial cells remains poorly understood. In our studies, we have identified putative binding sites for intestinal transcription factors Cdx1, -2 and GATA4 in the 5'-flanking region of the claudin-1 gene. Our further studies using full length and/or deletion mutant constructs in two different human colon cancer cell lines, SW480 and HCT116, showed key role of Cdx1, Cdx2 and GATA4 in the regulation of claudin-1 mRNA expression. However, overexpression of Cdx2 had the most potent effect upon claudin-1 mRNA expression and promoter activity. Also, in colon cancer patient samples, we observed a significant and parallel correlation between claudin-1 and Cdx2 expressions. Chromatin immunoprecipitation (ChIP) assay confirmed the Cdx2 binding with claudin-1 promoter in vivo. Using Cdx2 deletion mutant constructs, we further mapped the Cdx2 C-terminus domain to be important in the regulation of claudin-1 promoter activity. Interestingly, co-expression of activated β-catenin further induced the Cdx2-dependent upregulation of claudin-1 promoter activity while expression of the dominant negative (dn)-TCF-4 abrogated this activation. Taken together, we conclude that homeodomain transcription factors Cdx1, Cdx2 and GATA4 regulate claudin-1 gene expression in human colon cancer cells. Moreover, a functional crosstalk between Wnt-signaling and transcriptional activation related to caudal-related homeobox (Cdx) proteins and GATA-proteins is demonstrated in the regulation of claudin-1 promoter-activation.
0 Communities
5 Members
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15 MeSH Terms
Differential gene expression in normal esophagus and Barrett's esophagus.
Wang J, Qin R, Ma Y, Wu H, Peters H, Tyska M, Shaheen NJ, Chen X
(2009) J Gastroenterol 44: 897-911
MeSH Terms: Barrett Esophagus, CDX2 Transcription Factor, Databases, Genetic, Gene Expression, Gene Expression Profiling, Homeodomain Proteins, Humans, Immunohistochemistry, Oligonucleotide Array Sequence Analysis, Signal Transduction, Transcription Factors, Up-Regulation
Show Abstract · Added May 19, 2014
PURPOSE - As the premalignant lesion of human esophageal adenocarcinoma (EAC), Barrett's esophagus (BE) is characterized by intestinal metaplasia in the normal esophagus (NE). Gene expression profiling with microarray and serial analysis of gene expression (SAGE) may help us understand the potential molecular mechanism of human BE.
METHODS - We analyzed three microarray datasets (two cDNA arrays and one oligonucleotide array) and one SAGE dataset with statistical tools, significance analysis of microarrays (SAM) and SAGE(Poisson), to identify individual genes differentially expressed in BE. Gene set enrichment analysis (GSEA) was used to identify a priori defined sets of genes that were differentially expressed. These gene sets were grouped according to either certain signaling pathways (GSEA curated), or the presence of consensus binding sequences of known transcription factors (GSEA motif). Immunohistochemical staining (IHC) was used to validate differential gene expression.
RESULTS - Both SAM and SAGE(Poisson) identified 68 differentially expressed genes (55 BE genes and 13 NE genes) with an arbitrary cutoff ratio (> or =4-fold). With IHC on matched pairs of NE and BE tissues from 6 patients, these genes were grouped into 6 categories: category I (25 genes only expressed in BE), category II (5 genes only expressed in NE), category III (8 genes expressed more in BE than in NE), and category IV (2 genes expressed more in NE than in BE). Differential expression of the remaining genes was not confirmed by IHC either due to false discovery (category V), or lack of proper antibodies (category VI). Besides individual genes, the TGFbeta pathway and several transcription factors (CDX2, HNF1, and HNF4) were identified by GSEA as enriched pathways and motifs in BE. Apart from 9 target genes known to be up-regulated in BE, IHC staining confirmed up-regulation of 19 additional CDX1 and CDX2 target genes in BE.
CONCLUSION - Our data suggested an important role of CDX1 and CDX2 in the development of BE. The IHC-confirmed gene list will lead to future studies on the molecular mechanism of BE.
1 Communities
1 Members
0 Resources
12 MeSH Terms
Zonula occludens-1 (ZO-1) is involved in morula to blastocyst transformation in the mouse.
Wang H, Ding T, Brown N, Yamamoto Y, Prince LS, Reese J, Paria BC
(2008) Dev Biol 318: 112-25
MeSH Terms: Actins, Animals, Blastocyst, CDX2 Transcription Factor, Cadherins, Cell Differentiation, Electroporation, Female, Gene Expression Regulation, Developmental, Homeodomain Proteins, Male, Membrane Proteins, Mice, Morula, Octamer Transcription Factor-3, Phosphoproteins, Pregnancy, RNA, Small Interfering, Tight Junctions, Transcription Factors, Zonula Occludens-1 Protein, Zonula Occludens-2 Protein
Show Abstract · Added June 9, 2010
It is unknown whether or not tight junction formation plays any role in morula to blastocyst transformation that is associated with development of polarized trophoblast cells and fluid accumulation. Tight junctions are a hallmark of polarized epithelial cells and zonula occludens-1 (ZO-1) is a known key regulator of tight junction formation. Here we show that ZO-1 protein is first expressed during compaction of 8-cell embryos. This stage-specific appearance of ZO-1 suggests its participation in morula to blastocyst transition. Consistent with this idea, we demonstrate that ZO-1 siRNA delivery inside the blastomeres of zona-weakened embryos using electroporation not only knocks down ZO-1 gene and protein expressions, but also inhibits morula to blastocyst transformation in a concentration-dependent manner. In addition, ZO-1 inactivation reduced the expression of Cdx2 and Oct-4, but not ZO-2 and F-actin. These results provide the first evidence that ZO-1 is involved in blastocyst formation from the morula by regulating accumulation of fluid and differentiation of nonpolar blastomeres to polar trophoblast cells.
0 Communities
2 Members
0 Resources
22 MeSH Terms
Islet 1 (Isl1) expression is a reliable marker for pancreatic endocrine tumors and their metastases.
Schmitt AM, Riniker F, Anlauf M, Schmid S, Soltermann A, Moch H, Heitz PU, Klöppel G, Komminoth P, Perren A
(2008) Am J Surg Pathol 32: 420-5
MeSH Terms: Biomarkers, Tumor, CDX2 Transcription Factor, DNA-Binding Proteins, Gastrointestinal Neoplasms, Homeodomain Proteins, Humans, Immunohistochemistry, LIM-Homeodomain Proteins, Lung Neoplasms, Neoplasm Metastasis, Neuroendocrine Tumors, Pancreatic Neoplasms, Sensitivity and Specificity, Transcription Factors
Show Abstract · Added May 22, 2013
BACKGROUND - Tracing the origin of a metastasis of a neuroendocrine carcinoma is a challenge. The transcription factors Cdx2 and TTF1 have been found to be helpful in identifying well-differentiated neuroendocrine tumors of gastrointestinal and pulmonary origin, respectively. So far, such a marker is lacking for pancreatic neuroendocrine tumors (PETs) and metastases thereof. Islet1 (Isl1) is a transcription factor expressed in pancreatic islet cells. The aim of this study was (1) to test the specificity and sensitivity of Isl1 as a marker of PETs, and (2) to test the specificity and sensitivity of a panel of markers, including Isl1, Cdx2, and TTF1, for the localization of the primary.
DESIGN - One hundred eighty-eight primary gastroenteropancreatic and pulmonary endocrine tumors and 49 metastases thereof were examined. Immunohistochemistry using antibodies directed against Isl1, Cdx2, and TTF1 was performed and the staining results were scored semiquantitatively.
RESULTS - Isl1 proved to be a highly specific marker for pancreatic endocrine tumors. In 84 primary PET its specificity was 78.4% (sensitivity 74.3%) and in 18 metastases of PET the specificity reached 100% (sensitivity 77.8%). Strong Cdx2 staining showed a specificity for gastrointestinal origin of 83.9% (sensitivity 82%) in primary tumors and of 100% (sensitivity 40%) in metastases. Including weakly positive tumors lead to a decreased specificity but an increased sensitivity. TTF1 expression was detected in 2 PET and 1 ileal primary tumor only and was absent in all metastases of gastroenteropancreatic endocrine tumors.
CONCLUSIONS - Isl1 is a reliable marker of pancreatic endocrine tumors and metastases thereof. It shows a comparable sensitivity and specificity as Cdx2 as a marker of ileal and appendiceal neuroendocrine tumors and their metastases. TTF1 is very rarely expressed in well-differentiated gastroentero-PETs. Therefore, the panel of Isl1, Cdx2, and TTF1 seems useful for examining metastases of well-differentiated endocrine carcinomas of unknown origin.
0 Communities
0 Members
1 Resources
14 MeSH Terms
The homeodomain transcription factors Cdx1 and Cdx2 induce E-cadherin adhesion activity by reducing beta- and p120-catenin tyrosine phosphorylation.
Ezaki T, Guo RJ, Li H, Reynolds AB, Lynch JP
(2007) Am J Physiol Gastrointest Liver Physiol 293: G54-65
MeSH Terms: Animals, CDX2 Transcription Factor, Cadherins, Catenins, Cell Adhesion, Cell Adhesion Molecules, Cell Line, Tumor, Cell Movement, Colonic Neoplasms, Homeodomain Proteins, Humans, Mice, Phosphoproteins, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatases, Transcription Factors, Transfection, Tyrosine, beta Catenin
Show Abstract · Added March 5, 2014
The homeodomain transcription factors Cdx1 and Cdx2 are regulators of intestine-specific gene expression. They also regulate intestinal cell differentiation and proliferation; however, these effects are poorly understood. Previously, we have shown that expression of Cdx1 or Cdx2 in human Colo 205 cells induces a mature colonocyte morphology characterized by the induction of a polarized, columnar shape with apical microvilli and strong cell-cell adhesion. To elucidate the mechanism underlying this phenomenon, we investigated the adherens junction complex. Cdx1 or Cdx2 expression reduced Colo 205 cell migration and invasion in vitro, suggesting a physiologically significant change in cadherin function. However, Cdx expression did not significantly effect E-cadherin, alpha-, beta-, or gamma-catenin, or p120-catenin protein levels. Additionally, no alteration in their intracellular distribution was observed. Cdx expression did not alter the coprecipitation of beta-catenin with E-cadherin; however, it did reduce p120-catenin-E-cadherin coprecipitation. Tyrosine phosphorylation of beta- and p120-catenin is known to disrupt E-cadherin-mediated cell adhesion and is associated with robust p120-catenin/E-cadherin interactions. We specifically investigated beta- and p120-catenin for tyrosine phosphorylation and found that it was significantly diminished by Cdx1 or Cdx2 expression. We restored beta- and p120-catenin tyrosine phosphorylation in Cdx2-expressing cells by knocking down the expression of protein tyrosine phosphatase 1B and noted a significant decline in cell-cell adhesion. We conclude that Cdx expression in Colo 205 cells induces E-cadherin-dependent cell-cell adhesion by reducing beta- and p120-catenin tyrosine phosphorylation. Ascertaining the mechanism for this novel Cdx effect may improve our understanding of the regulation of cell-cell adhesion in the colonic epithelium.
1 Communities
1 Members
0 Resources
20 MeSH Terms
Altered nuclear transfer in stem-cell research - a flawed proposal.
Melton DA, Daley GQ, Jennings CG
(2004) N Engl J Med 351: 2791-2
MeSH Terms: Animals, CDX2 Transcription Factor, Cell Line, Embryo, Mammalian, Embryonic Development, Homeodomain Proteins, Humans, Mice, Mutation, Nuclear Transfer Techniques, Pluripotent Stem Cells, Research Embryo Creation, Stem Cells, Transcription Factors
Added May 7, 2015
0 Communities
0 Members
1 Resources
14 MeSH Terms