The Caudal-related Homeodomain Protein Cdx1 Inhibits Proliferation of Intestinal Epithelial Cells by Down-regulation of D-type Cyclins

Lynch, John P.; Suh, EunRan; Silberg, Debra G.; Rulyak, S.; Blanchard, Nadine; Traber, Peter G.

doi:10.1074/jbc.275.6.4499

Cited by 61 publications

(65 citation statements)

References 34 publications

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“…Whole-cell extracts were prepared as described (22,23,34). Briefly, cells were washed twice in PBS, removed with rubber cell scraper, pelleted, and then resuspended in 80 AL of buffer A (1Â PBS with 2 Ag/mL aprotinin, 2 Ag/mL leupeptin, 0.2 mmol/L phenylmethylsulfonyl fluoride, 1 mmol/L NaF, 1 mmol/L NaVO 4 ).…”

Section: Western Blotsmentioning

confidence: 99%

“…Sequences of these oligonucleotides are listed in Table 1. EMSAs were done as described previously (22,34). To do supershift assay, the binding mixtures were incubated for 10 min at room temperature in the presence of 1 AL of Cdx1 (CPSP) or Cdx2 (Cdx2-88) antibodies before electrophoresis.…”

Section: Electrophoretic Mobility Shift Assaysmentioning

confidence: 99%

“…For reporter assays, a DNA transfection mixture was prepared consisting of 0.1 to 5 Ag of the reporter construct and 50 ng of pRL-CMV Renilla (Promega). pRC/CMV-Cdx1 or pRC/CMV-Cdx2 expression vectors were used to transiently express Cdx1 or Cdx2 and have been previously described (22,23,34). pCR2.1 vector (Invitrogen) was used to equalize the amount of transfected DNA.…”

Section: Promoter-reporter Studiesmentioning

confidence: 99%

“…We conclude that the DSC2 gene is a transcriptional target for the intestine-specific transcription factors Cdx1 and Cdx2. Regulation of adherens, tight, and now desmosomal junctions by Cdx contributes to normal intestinal epithelial columnar morphology Transient Cdx1 expression was induced in DLD1 colon cancer cells using either an adenoviral vector (AdCdx1 ) or electroporation, as previously described (22,34). DSC2 mRNA levels were then quantified at 48 h by quantitative real-time SYBR Green reverse transcription-PCR.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Western Blotsmentioning

confidence: 99%

Section: Electrophoretic Mobility Shift Assaysmentioning

confidence: 99%

Section: Promoter-reporter Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…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).…”

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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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Expression of homeobox‐containing genes in cDNA libraries derived from cattle oocytes and preimplantation stage embryo

Ponsuksili

Wimmers

Adjaye

et al. 2001

Molecular Reproduction Devel

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The homeobox-containing gene family plays a pivotal role in regulating, patterning, and axial morphogenesis in the developing embryo. But there is still very little known about the expression and function of these genes in mammalian oocytes and preimplantation stage embryos. In this study we have used degenerate primers corresponding to the highly conserved regions of Antennapedia class homeodomains as a rapid and an efficient method to survey bovine cDNA libraries derived from unfertilised oocytes, single 2-cell, 4-cell, 8-cell, morula, and blastocyst stage embryos for the presence of homeobox sequences. Our results provide, for the first time, evidence for the transcription of Hoxa3 and Hoxd1 in oocytes; Cdx1 and Cdx2 in the 2-cell; Cdx1, Hoxa1, Hoxd1, and Hoxd4 in the 4-cell; Cdx1, Hoxa1, and Hoxc9 in the 8-cell; Cdx2, Hoxb9, and Hoxc9 in the morula; Cdx2, Hoxb7, Hoxb9, and Hoxc9 in blastocyst stage cattle embryos. These are candidate genes for the developmental capacity of in vivo and in vitro produced bovine embryos.

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The Caudal-related Homeodomain Protein Cdx1 Inhibits Proliferation of Intestinal Epithelial Cells by Down-regulation of D-type Cyclins

Abstract: Cdx1 is a homeodomain transcription factor that regulates intestine-specific gene expression. Experimental evidence suggests that Cdx1 may be involved in cell cycle regulation, but its role is ill defined and the mechanisms have not been explored. We used stable transfec-

Cited by 61 publications

References 34 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, a dispensable homeobox gene for gut development with limited effect in intestinal cancer

Expression of homeobox‐containing genes in cDNA libraries derived from cattle oocytes and preimplantation stage embryo

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