Cdx1 promotes differentiation in a rat intestinal epithelial cell line

Soubeyran, Philippe; André, Frédéric; Lissitzky, Jean‐Claude; Mallo, Gustavo V.; Moucadel, Virginie; Roccabianca, Monique; Rechreche, Hocine; Marvaldi, Jacques; Đikić, Ivan; Dagorn, Jean–Charles; Iovanna, Juan

doi:10.1016/s0016-5085(99)70283-0

Cited by 111 publications

(94 citation statements)

References 52 publications

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“…1A). The induction of desmosomes by Cdx has been noted by us and others in the past (17,20,21). However, the mechanism by which this occurs remains unknown.…”

Section: Resultsmentioning

confidence: 87%

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Repression of the Desmocollin 2 Gene Expression in Human Colon Cancer Cells Is Relieved by the Homeodomain Transcription Factors Cdx1 and Cdx2

Funakoshi

Ezaki

Kong

et al. 2008

Molecular Cancer Research

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Desmosomes are intracellular junctions that provide strong cell-cell adhesion in epithelia and cardiac muscle. Their disruption causes several human diseases and contributes to the epithelial-to-mesenchymal transition observed in cancer. Desmocollin 2 (DSC2) is a cadherin superfamily member and a critical component of desmosomes found in intestinal epithelium. However, the mechanism regulating DSC2 gene expression in intestinal cells is not known. Cdx1 and Cdx2 are homeodomain transcription factors that regulate intestine-specific gene expression. Cdx expression in the past has been associated with the induction of desmosomes. We now show that the DSC2 gene is a transcriptional target for Cdx1 and Cdx2. Colon cancer cell lines retaining Cdx2 expression typically express DSC2. Restoration of Cdx expression in Colo 205 cells induced DSC2 mRNA and protein and the formation of desmosomes. The 5 ¶-flanking region of the DSC2 promoter contains two consensus Cdx-binding sites. Electrophoretic mobility shift assays show that Cdx1 and Cdx2 bind these sites in vitro, and chromatin immunoprecipitation confirmed Cdx2 binding in vivo. DSC2 promoter truncations established that these regions are Cdx responsive. The truncations also identify a region of the promoter in which potent transcriptional repressors act. This repressor activity is relieved by Cdx binding. We conclude that the homeodomain transcription factors Cdx1 and Cdx2 regulate DSC2 gene expression in intestinal epithelia by reversing the actions of a transcriptional repressor. The regulation of desmosomal junctions by Cdx contributes to normal intestinal epithelial columnar morphology and likely antagonizes the epithelial-to-mesenchymal transition necessary for the metastasis of colon cancer cells in humans.

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“…1A). The induction of desmosomes by Cdx has been noted by us and others in the past (17,20,21). However, the mechanism by which this occurs remains unknown.…”

Section: Resultsmentioning

confidence: 87%

“…In the present study, we showed that the intestine-specific transcription factors Cdx1 and Cdx2 directly regulate DSC2 gene expression. Enhanced DSC2 protein levels may contribute to the increased desmosome formation observed after the expression of Cdx1 or Cdx2 in some cell lines (17,18,20,21).…”

Section: Discussionmentioning

confidence: 99%

Repression of the Desmocollin 2 Gene Expression in Human Colon Cancer Cells Is Relieved by the Homeodomain Transcription Factors Cdx1 and Cdx2

Funakoshi

Ezaki

Kong

et al. 2008

Molecular Cancer Research

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“…The homeodomain proteins Cdx1 and Cdx2 are wellrecognized regulators of intestine-specific gene expression and enterocyte differentiation (Suh et al, 1994;Suh and Traber, 1996;Taylor et al, 1997;Freund et al, 1998;Soubeyran et al, 1999). Cdx1 and Cdx2 are important transcriptional activators, promoting the intestine-specific expression of a number of genes including sucrase isomaltase, colon carbonic anhydrase 1, and intestinal phospholipase A/lyso-phospholipase (IPAL) (Suh et al, 1994;Taylor et al, 1997;Drummond et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Cdx1 inhibits the proliferation of human colon cancer cells by reducing cyclin D1 gene expression

et al. 2003

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The transcription factor Cdx1 regulates intestine-specific gene expression and enterocyte differentiation. It has been hypothesized to play a role in regulating intestinal cell proliferation; however, the mechanism for this effect remains elusive. In a prior study, we demonstrated that Cdx1 expression reduced the proliferation of a nontransformed intestinal cell line. This study tests the hypothesis that Cdx1 expression inhibits colon cancer cell proliferation by reducing cyclin D1 gene expression. Cdx1 expression markedly reduced cancer cell proliferation and DNA synthesis and induced an accumulation of cells in G0/G1. A transcriptionally inactive Cdx1 mutant could not elicit this effect, suggesting that it required Cdx1 transcriptional activity. Cdx1 expression increased the hypophosphorylation of the retinoblastoma (pRb) and p130 proteins. Reductions in G1 cyclin-dependant kinase (cdk) activity accompanied this effect. Cyclin D1 mRNA and protein levels were diminished by Cdx1 expression. Restoration of cyclin D1 expression reversed the G0/G1 block and induced pRb hyperphosphorylation. Lastly, Cdx1 expression did not alter cyclin D1 mRNA stability but did reduce cyclin D1 promoter activity, suggesting that Cdx1 acts to diminish cyclin D1 gene transcription. We conclude that Cdx1 reduces the proliferation of human colon cancer cells by reducing cyclin D1 gene transcription.

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“…Although the role of Cdx1 has been unveiled in body axis patterning (Subramanian et al, 1995), its relevance remains elusive in the gut. In intestinal cells cultured in vitro, Cdx1 stimulates differentiation (Soubeyran et al, 1999) and either stimulates (Lorentz et al, 1997;Soubeyran et al, 1999) or inhibits proliferation (Lynch et al, 2000). In human colon cancers, Cdx1 expression increases in few adenomas and carcinomas but decreases or is even lost in the majority of carcinomas (Mallo et al, 1997;Silberg et al, 1997;Vider et al, 1997;Domon-Dell et al, 2003;Pilozzi et al, 2004).…”

mentioning

confidence: 99%

Cdx1, a dispensable homeobox gene for gut development with limited effect in intestinal cancer

et al. 2008

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The homeobox gene Cdx1 is involved in anteroposterior patterning in embryos and its expression selectively persists in the intestinal epithelium throughout life. In human colon cancers, Cdx1 is overexpressed in few cases and lost in the majority of adenocarcinomas. We used mouse models of gain and loss-of-function to investigate the role of Cdx1 in intestinal development and cancers. Transgenic mice overexpressing Cdx1 and knockout mice exhibited a morphologically normal intestine. Cell proliferation, specification into the four differentiated lineages and migration along the crypt-villus axis were unchanged compared to wild-type mice. Changing Cdx1 caused an inverse and dose-dependent modification of the expression of the paralogous gene Cdx2, indicating that Cdx1 fine-tunes Cdx2 activity. Transgenenic and knockout mice failed to spontaneously develop tumours. Overexpressing Cdx1 was without incidence on the frequency of intestinal tumours induced chemically by azoxymethane treatment or genetically in Apc D14/ þ mice. However, it augmented the severity of the tumours in Apc D14/ þ mice. Inversely, the loss-of-function of Cdx1 in knockout mice was without incidence on the growth of tumours induced by azoxymethane. We conclude that Cdx1 is dispensable for intestinal development and that its overexpression could increase malignancy in early stages of tumourigenesis.

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Cdx1 promotes differentiation in a rat intestinal epithelial cell line

Cited by 111 publications

References 52 publications

Repression of the Desmocollin 2 Gene Expression in Human Colon Cancer Cells Is Relieved by the Homeodomain Transcription Factors Cdx1 and Cdx2

Repression of the Desmocollin 2 Gene Expression in Human Colon Cancer Cells Is Relieved by the Homeodomain Transcription Factors Cdx1 and Cdx2

Cdx1 inhibits the proliferation of human colon cancer cells by reducing cyclin D1 gene expression

Cdx1, a dispensable homeobox gene for gut development with limited effect in intestinal cancer

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