Cell type-specific autoregulation of the Caudal-related homeobox gene Cdx-2/3.
The caudal-related homeobox gene Cdx-2/3 is a critical "master" control gene in embryogenesis. Mice heterozygous for a null mutation in Cdx-2/3 exhibit multiple malfunctions including tail abnormalities, stunted growth, a homeotic shift in vertebrae, and the development of multiple intestinal adenomatous polyps, indicating that Cdx-2/3 is haplo-insufficient. In vitro studies have identified more than a half-dozen downstream target genes expressed in pancreatic and intestinal cells for this transcription factor. We have examined the transcriptional properties of the mouse Cdx-2/3 promoter. This promoter could be autoregulated in pancreatic and intestinal cells that express endogenous Cdx-2/3. In contrast, Cdx-2/3 transfection represses the Cdx-2/3 promoter in fibroblasts, which do not express endogenous Cdx-2/3. Since Cdx-2/3 activates proglucagon gene promoter in both pancreatic and intestinal cells and in fibroblasts, we suggest that some, yet to be identified, cell type-specific components are required for activating selected target gene promoters of Cdx-2/3, including the Cdx-2/3 promoter itself. Cdx-2/3 binds to the TATA box and another AT-rich motif, designated as DBS, within an evolutionarily conserved proximal element of the Cdx-2/3 promoter. The DBS motif is critical for the autoregulation, whereas the TATA box may act as an attenuating element for the autoregulatory loop. Finally, overexpression of Cdx-2/3 in a pancreatic cell line activated the expression of the endogenous Cdx-2/3. Taken together, our results indicate that the dose-dependent phenotype of Cdx-2/3 expression on its downstream targets in vivo could be regulated initially via a transcriptional network involving cell type-specific autoregulation of the Cdx-2/3 promoter.
Xu
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Oncology Research Laboratory, The Toronto Hospital, University of Toronto, Toronto, Ontario M5G 2M1, Canada.
Li
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H
Jin
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D016475:3T3 Cells; D020856:AT Rich Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D064026:Calbindins; D002460:Cell Line; D006224:Cricetinae; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015342:DNA Probes; D005786:Gene Expression Regulation; D005801:Genes, Homeobox / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D016385:TATA Box; D015534:Trans-Activators
D000071616:CDX2 Transcription Factor; D064026:Calbindins; D015342:DNA Probes; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D064030:S100 Calcium Binding Protein G; D015534:Trans-Activators; D004247:DNA; D008156:Luciferases; D005982:Glutathione Transferase