Isolation and characterization of the murine homeobox gene Cdx-1. Regulation of expression in intestinal epithelial cells.

Hu, Yinling; Kazenwadel, Jan; James, Rosemary

doi:10.1016/s0021-9258(19)74240-9

Cited by 56 publications

(6 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is worth noting that the decrease of Cdx1 expression by antisense RNA as well as the overexpression of Cdx2 result in an inhibition of cell proliferation. This, together with the fact that the level of Cdx1 mRNA is reduced in Cdx2-overexpressing cells, may suggest a negative regulatory effect of the CDX2 protein on Cdx1 mRNA expression in enterocytes that pass the crypt-villus junction; positive and negative regulatory elements have been reported in the Cdx1 gene promoter (Hu et al, 1993). A direct interaction between the CDX2 protein and promoter elements of enterocytic markers of differentiation has been demonstrated (Suh et al, 1994;Drummond et al, 1996;Lee et al, 1996;Lambert et al, 1996;Troelsen et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…In Drosophila , caudal is involved in anterio-posterior patterning (Macdonald and Struhl, 1986;Mlodzik and Gehring, 1987). In mammals, Cdx1 was the first homeobox gene discovered in endodermal tissues (Duprey et al, 1988;Hu et al, 1993); it exhibits an increasing gradient expression along the longitudinal axis of gut (James and Kazenwadel, 1991;Freund et al, 1992), and the protein is predominantly expressed in undifferentiated crypt cells (Silberg et al, 1997). Cdx2 , another caudal -related gene present in the intestine, encodes a nuclear transcriptional factor that is expressed in the differentiated enterocytes (James et al, 1994) and binds cis-elements present in the gene promoters of enterocytic markers such as sucrase-isomaltase (SI) 1 , lactase-phlorizin hydrolase (LPH), apolipoprotein B, carbonic anhydrase 1, and calbindin D9K (Suh et al, 1994;Drummond et al, 1996;Lambert et al, 1996;Lee et al, 1996;Troelsen et al, 1997).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Key Role of the Cdx2 Homeobox Gene in Extracellular Matrix–mediated Intestinal Cell Differentiation

Lorentz

Duluc

Arcangelis

et al. 1997

The Journal of Cell Biology

256

210

View full text Add to dashboard Cite

To explore the role of homeobox genes in the intestine, the human colon adenocarcinoma cell line Caco2-TC7 has been stably transfected with plasmids synthesizing Cdx1 and Cdx2 sense and antisense RNAs. Cdx1 overexpression or inhibition by antisense RNA does not markedly modify the cell differentiation markers analyzed in this study. In contrast, Cdx2 overexpression stimulates two typical markers of enterocytic differentiation: sucrase-isomaltase and lactase. Cells in which the endogenous expression of Cdx2 is reduced by antisense RNA attach poorly to the substratum. Conversely, Cdx2 overexpression modifies the expression of molecules involved in cell–cell and cell–substratum interactions and in transduction process: indeed, E-cadherin, integrin-β4 subunit, laminin-γ2 chain, hemidesmosomal protein, APC, and α-actinin are upregulated. Interestingly, most of these molecules are preferentially expressed in vivo in the differentiated villi enterocytes rather than in crypt cells. Cdx2 overexpression also results in the stimulation of HoxA-9 mRNA expression, an homeobox gene selectively expressed in the colon. In contrast, Cdx2-overexpressing cells display a decline of Cdx1 mRNA, which is mostly found in vivo in crypt cells. When implanted in nude mice, Cdx2-overexpressing cells produce larger tumors than control cells, and form glandular and villus-like structures.Laminin-1 is known to stimulate intestinal cell differentiation in vitro. In the present study, we demonstrate that the differentiating effect of laminin-1 coatings on Caco2-TC7 cells is accompanied by an upregulation of Cdx2. To further document this observation, we analyzed a series of Caco2 clones in which the production of laminin-α1 chain is differentially inhibited by antisense RNA. We found a positive correlation between the level of Cdx2 expression, that of endogenous laminin-α1 chain mRNA and that of sucrase-isomaltase expression in these cell lines.Taken together, these results suggest (a) that Cdx1 and Cdx2 homeobox genes play distinct roles in the intestinal epithelium, (b) that Cdx2 provokes pleiotropic effects triggering cells towards the phenotype of differentiated villus enterocytes, and (c) that Cdx2 expression is modulated by basement membrane components. Hence, we conclude that Cdx2 plays a key role in the extracellular matrix–mediated intestinal cell differentiation.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Key Role of the Cdx2 Homeobox Gene in Extracellular Matrix–mediated Intestinal Cell Differentiation

Lorentz

Duluc

Arcangelis

et al. 1997

The Journal of Cell Biology

256

210

View full text Add to dashboard Cite

show abstract

“…The above data suggested that the Cdx1 promoter responds to Wnt/␤-catenin signaling, and that this effect maps to sequences between Ϫ185 and Ϫ38 nucleotides upstream of the Cdx1 transcription start site (numbered according to Hu et al, 1993). Examination of these sequences revealed the presence of a near-consensus LEF/TCF binding motif (Clevers and van de Wetering, 1997) at position Ϫ113 to Ϫ104 (denoted denoted LRE1), with a second potential element (designated LRE2) at position Ϫ82 to Ϫ70 (Fig.…”

Section: Wnt Signaling Directly Activates the Cdx1 Promotermentioning

confidence: 96%

Multiple Pathways Governing Cdx1 Expression during Murine Development

Prinos

Joseph

et al. 2001

Developmental Biology

122

View full text Add to dashboard Cite

Cdx1 encodes a mammalian homeobox gene involved in vertebral patterning. Retinoic acid (RA) is likewise implicated in vertebral patterning. We have previously shown that Cdx1 is a direct retinoid target gene, suggesting that Cdx1 may convey some of the effects of retinoid signaling. However, RA appears to be essential for only early stages of Cdx1 expression, and therefore other factors must be involved in maintaining later stages of expression. Based on function and pattern of expression, Wnt family members, in particular Wnt3a, are candidates for regulation of expression of Cdx1. Consistent with this, we confirm prior results which demonstrated that Cdx1 can be directly regulated by Wnt signaling, and identify functional LEF/TCF response motifs essential for this response. We also find that Cdx1 expression is markedly attenuated in a stage- and tissue-specific fashion in the Wnt3a hypomorph vestigial tail, and present data demonstrating that Wnt3a and RA synergize strongly to activate Cdx1. Finally, we show that Cdx1 positively regulates its own expression. These data prompt a model whereby retinoid and Wnt signaling function directly and synergistically to initiate Cdx1 expression in the caudal embryo. Expression is then maintained, at least in part, by an autoregulatory mechanism at later stages.

show abstract

“…The homeobox encodes for a protein domain that interacts with specific DNA sequences, allowing members of this gene family to regulate transcriptional initiation as either an activator or repressor. The caudal-related homeobox genes are a non-clustered family, including three members in mouse, Cdx1 (4), Cdx2 (5,6) and Cdx4 (7). Each of these genes has a complex pattern of expression in the developing mouse embryo (7)(8)(9), but Cdx1 and Cdx2 are highly expressed in the adult mouse only in the epithelium of the small intestine and colon (10,11).…”

Section: Introductionmentioning

confidence: 99%

Activation of enhancer elements by the homeobox gene Cdx2 is cell line specific

Taylor

Levy

Suh

et al. 1997

Nucleic Acids Research

View full text Add to dashboard Cite

Cdx2 is a caudal-related homeodomain transcription factor that is expressed in complex patterns during mouse development and at high levels in the intestinal epithelium of adult mice. Cdx2 activates transcription of intestinal gene promoters containing specific binding sites. Moreover, Cdx2 has been shown to induce intestinal differentiation in cell lines. In this study, we show that Cdx2 is able to bind to two well defined enhancer elements in the HoxC8 gene. We then demonstrate that Cdx2 is able to activate transcription of heterologous promoters when its DNA binding element is placed in an enhancer context. Furthermore, the ability to activate enhancer elements is cell-line dependent. When the Cdx2 activation domain was linked to the Gal4 DNA binding domain, the chimeric protein was able to activate Gal4 enhancer constructs in an intestinal cell line, but was unable to activate transcription in NIH3T3 cells. These data suggest that there are cell-specific factors that allow the Cdx2 activation domain to function in the activation of enhancer elements. We hypothesize that either a co-activator protein or differential phosphorylation of the activation domain may be the mechanism for intestinal cell line-specific function of Cdx2 and possibly in other tissues in early development.

show abstract

Isolation and characterization of the murine homeobox gene Cdx-1. Regulation of expression in intestinal epithelial cells.

Cited by 56 publications

References 60 publications

Key Role of the Cdx2 Homeobox Gene in Extracellular Matrix–mediated Intestinal Cell Differentiation

Key Role of the Cdx2 Homeobox Gene in Extracellular Matrix–mediated Intestinal Cell Differentiation

Multiple Pathways Governing Cdx1 Expression during Murine Development

Activation of enhancer elements by the homeobox gene Cdx2 is cell line specific

Contact Info

Product

Resources

About