<i>Cdx1</i> Autoregulation Is Governed by a Novel Cdx1-LEF1 Transcription Complex

Béland, Mélanie; Pilon, Nicolas; Houle, Martin; Oh, Karen Y.; Sylvestre, Jean-René; Prinos, Panagiotis; Lohnes, David

doi:10.1128/mcb.24.11.5028-5038.2004

Cited by 71 publications

(104 citation statements)

References 63 publications

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“…Persistence of metaplastic changes after removal of triggering agents such as H. pylori indicates that expression of a key inducer of metaplasia must have been maintained in the absence of triggering agents. CDX1 fits this idea in that it establishes an autoregulatory network to maintain its own expression (22). However, the mechanism by which ectopic CDX1 provokes metaplastic changes has remained poorly understood.…”

Section: Discussionmentioning

confidence: 95%

CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5

Fujii

Yoshihashi

Suzuki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

121

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Intestinal metaplasia of the stomach, a mucosal change characterized by the conversion of gastric epithelium into an intestinal phenotype, is a precancerous lesion from which intestinal-type gastric adenocarcinoma arises. Chronic infection with Helicobacter pylori is a major cause of gastric intestinal metaplasia, and aberrant induction by H. pylori of the intestine-specific caudal-related homeobox (CDX) transcription factors, CDX1 and CDX2, plays a key role in this metaplastic change. As such, a critical issue arises as to how these factors govern the cell-and tissue-type switching. In this study, we explored genes directly activated by CDX1 in gastric epithelial cells and identified stemness-associated reprogramming factors SALL4 and KLF5. Indeed, SALL4 and KLF5 were aberrantly expressed in the CDX1 + intestinal metaplasia of the stomach in both humans and mice. In cultured gastric epithelial cells, sustained expression of CDX1 gave rise to the induction of early intestinal-stemness markers, followed by the expression of intestinal-differentiation markers. Furthermore, the induction of these markers was suppressed by inhibiting either SALL4 or KLF5 expression, indicating that CDX1-induced SALL4 and KLF5 converted gastric epithelial cells into tissue stem-like progenitor cells, which then transdifferentiated into intestinal epithelial cells. Our study places the stemness-related reprogramming factors as critical components of CDX1-directed transcriptional circuitries that promote intestinal metaplasia. Requirement of a transit through dedifferentiated stem/progenitor-like cells, which share properties in common with cancer stem cells, may underlie predisposition of intestinal metaplasia to neoplastic transformation.CagA | Wnt | β-catenin

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Section: Discussionmentioning

confidence: 95%

CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5

Fujii

Yoshihashi

Suzuki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

121

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“…By E8.5, Cdx1 expression is maintained in the caudal embryo through mechanisms involving both Wnt signaling (8) and autoregulation (9). RA, however, is absent in this region at this stage but is found in a more anterior domain in the prospective trunk (10).…”

Section: Cdx1mentioning

confidence: 99%

Chicken Ovalbumin Upstream Promoter-Transcription Factor Members Repress Retinoic Acid-induced Cdx1 Expression

Béland

Lohnes

2005

Journal of Biological Chemistry

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It is well established that Hox genes are key players in specifying positional identity along the anterior-posterior axis and are targets of diverse transcription factors implicated in axial patterning. Members of the CDX family (CDX1, -2, and -4) are among such effectors of Hox expression as pertains to vertebral patterning in the mouse. Cdx members are themselves targets of signaling molecules that are also implicated in axial patterning, including retinoic acid (RA) and certain members of Wnt and fibroblast growth factor families. In this regard, we have previously shown that, in the mouse, Cdx1 is directly regulated by RA at the late primitive streak stage (embryonic day (E) 7.5) through a RA response element in the proximal Cdx1 promoter. At E8.5, Cdx1 expression remains essentially limited to the posterior embryo. RA, however, is excluded from the caudal embryo at this later stage, but is found in a more anterior domain encompassing the prospective trunk region. These observations suggest the existence of a repressor mechanism that prevents expression of Cdx1 in these anterior domains of retinoid signaling at E8.5. In the present study, we present evidence suggesting that chicken ovalbumin upstream promoter-transcription factor (COUP-TF) members antagonize RA-induced Cdx1 expression by competing with retinoid X receptor-retinoic acid receptor heterodimers for binding to the Cdx1 RA response element. Consistent with this, in situ hybridization analysis revealed that COUP-TFs are highly expressed in the anterior embryo in domains where Cdx1 transcripts are excluded. Together with other data, these findings suggest a model by which COUP-TF expression is induced by RA in the trunk region as a negative feedback mechanism to restrict Cdx1 expression to the caudal embryo.

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“…FLAG-tagged Cdx1 expression vector has been described previously (46). FLAG-tagged EnRCdx1 and EnR constructs were generated by subcloning the relevant sequences into a modified pCEP4 plasmid (Invitrogen) (46). Cdx1, Cdx2, Cdx4, EnR, and EnRCdx1 bicistronic expression vectors were generated by subcloning the respective cDNA into the pIRES2-EGFP vector (Clontech).…”

Section: Methodsmentioning

confidence: 99%

“…S1). FLAG-tagged Cdx1 expression vector has been described previously (46). FLAG-tagged EnRCdx1 and EnR constructs were generated by subcloning the relevant sequences into a modified pCEP4 plasmid (Invitrogen) (46).…”

Section: Methodsmentioning

confidence: 99%

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Caudal-related Homeobox (Cdx) Protein-dependent Integration of Canonical Wnt Signaling on Paired-box 3 (Pax3) Neural Crest Enhancer

Ferras

Coutaud

Samani

et al. 2012

Journal of Biological Chemistry

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Cdx1 Autoregulation Is Governed by a Novel Cdx1-LEF1 Transcription Complex

Cited by 71 publications

References 63 publications

CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5

CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5

Chicken Ovalbumin Upstream Promoter-Transcription Factor Members Repress Retinoic Acid-induced Cdx1 Expression

Caudal-related Homeobox (Cdx) Protein-dependent Integration of Canonical Wnt Signaling on Paired-box 3 (Pax3) Neural Crest Enhancer

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