Suppressor and Activator Functions Mediated by a Repeated Heptad Sequence in the Liver Fatty Acid-binding Protein Gene (Fabpl)

Abstract

Epithelial cells that line the intestine and the nephrons of the kidney share many common functions. The molecular mechanisms that regulate gene transcription within and between these epithelia are largely uncharacterized. The "liver" fatty acid-binding protein gene (Fabpl) 1 provides a model for investigating these mechanisms.In the adult mouse and rat, Fabpl is transcribed in hepatocytes and in polarized absorptive enterocytes, the principal epithelial cell lineage of the small intestine (1). Fabpl exhibits a cephalocaudal gradient of expression within the intestine; highest levels of its mRNA and protein products are encountered in differentiated enterocytes that overlie villi located in the middle third of the small intestine; levels diminish as one moves proximally or distally. The gene is silent in the gastric and distal colonic epithelium of both species and in all other epithelia not associated with the gastrointestinal tract.The contribution of cis-acting suppressors to maintaining this pattern of expression was revealed from studies in transgenic mice (1). Seven fusion genes were produced by sequential deletions of the proximal 4000 nucleotides of rat Fabpl's 5Ј-nontranscribed domain and linkage of each truncated product to nucleotides ϩ3 to ϩ2150 of the human growth hormone (hGH) gene. The cellular and spatial patterns of expression of each fusion gene were defined in multiple pedigrees of adult

Bmp signaling is required for intestinal growth and morphogenesis

“…To test this hypothesis, we generated 2 transgenic mouse lines that express noggin under the control of a variant of the rat Fabp1 4ϫ at Ϫ132 promoter that drives expression in the large intestine (Simon et al, 1997). Both lines show abnormalities of the large intestine, with epithelial and mesenchymal hyperplasia and the formation of polyps lined by ectopic proliferating glands ( Fig.…”

“…The Fabp1-Noggin transgenes were constructed by cloning the coding sequence of Xenopus Noggin from pNoggin5Ј (Smith and Harland, 1992) into pLPNDon containing the Fabp1 Ϫ596 to ϩ21 promoter of the rat liver fatty acid binding protein gene (Fabp1) for expression in the small intestine and into pJ51 containing the Fabp1 4ϫ at Ϫ132 promoter for large intestinal expression (Simon et al, 1993(Simon et al, , 1997. The transgene was released from the vector backbone and injected into one cell (B6D2) F2 embryos.…”

“…Here, we describe transgenic mouse models based on the misexpression of noggin under the control of two versions of the well-characterized promoter of the rat liver fatty acid binding protein gene (Fabp1) (Simon et al, 1993(Simon et al, , 1997. One version (Fabp1 4ϫ at Ϫ132 ) drives expression in the large intestine, the region where human gastrointestinal cancers most frequently arise.…”

Role of c-Myc in intestinal tumorigenesis of the Apc min/+ mouse1

“…32 Mice carrying the floxed c-Myc alleles (c-Myc fl/fl ) 33 were bred to transgenic mice which express Cre recombinase under the control of transcriptional regulatory elements derived from a liver fatty acid-binding protein gene (Fabpl 4x at -132 ). 34 Immunofluorescent staining for Cre recombinase. The proximal, middle and distal areas of the small intestine were opened and their luminal contents were removed by washing the tissues in phosphate-buffered saline (PBS).…”

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

“…The promoter fragment required for transactivation of the Fabp gene in the intestinal mucosa is well characterized 32 and has been used by several investigators to drive the expression of cDNAs of interest in an intestine-specific manner. 33 Because fatty acids that are present following meal ingestion represent a physiologic stimulus, we used the functional Fabp promoter to drive the expression of hGAS in the intestinal mucosa.…”