Comparison of Intestinal Phospholipase A/Lysophospholipase and Sucrase-Isomaltase Genes Suggests a Common Structure for Enterocyte-Specific Promoters

Abstract

Intestinal phospholipase A/lysophospholipase (IPAL) is an intestine-specific brush-border enzyme expressed during development and along the intestinal crypt-villus axis in a pattern similar to another well characterized brush-border enzyme, sucrase-isomaltase (SI). A tissue-specific DNase I hypersensitive site was identified in chromatin from intestinal nuclei immediately upstream from the transcriptional start site of the IPAL gene. Footprinting analysis showed that two DNA elements within the IPAL promoter were protected by intestinal nuclear proteins. The IPAL-FP1 element was shown to be a monomer binding site for Cdx1 and Cdx2, intestine-specific homeobox proteins. Moreover, this site was important for transcriptional activation of the promoter in intestinal cell lines via interaction with Cdx proteins. Nuclear proteins from both liver and intestine interacted with the IPAL-FP2 element, forming a complex consistent with binding to HNF1. Cdx and HNF1 binding sites have also been shown to be the two major regulatory elements responsible for transcriptional activation of the SI gene promoter, which directs intestine-specific transcription in transgenic mice. These findings suggest that enterocyte genes that are expressed in similar developmental patterns may be regulated by the interaction of common DNA elements and their associated transcription factors.

Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation

“…First, we compared the ability of overexpressed Cdx2 wild-type and 4S>A mutant to stimulate the expression of luciferase driven by Cdx2-responsive promoters. Figure 4a shows the results obtained with HCT 116 cotransfected with IPAL-Luc (Taylor et al, 1997a) and increasing doses of the plasmids encoding Cdx2 wild-type or the mutant 4S>A. As expected, wild-type Cdx2 stimulated expression of this reporter in a dose-dependent manner.…”

Lewis Type 1 Antigen Synthase (β3Gal-T5) Is Transcriptionally Regulated by Homeoproteins

“…Many intestine-specific genes, such as those for sucrase-isomaltase (SI) (13,14), lactase-phlorizin hydrolase (LPH) (13,(15)(16)(17), intestine phospholipase A/lysophospholipase (18), and claudin-2 (19) have been demonstrated to be transcriptionally regulated by Cdx proteins. It has also been reported that the Cdx family is involved in intestinal carcinogenesis, differentiation, and morphogenesis using several experimental approaches (20 -23).…”

“…The intestine phospholipase A/lysophospholipase promoter also has binding sites for Cdx and HNF1 (18), although it has yet to be reported whether the HNF1 site is functional or not. The promoter regions of these genes share certain features, namely HNF1-, Cdx-, and GATAbinding sites within 200 bp upstream of their transcription initiation site (Fig.…”

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

“…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).…”

“…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). Cdx1 and Cdx2 also promote differentiation of intestinal cells (Suh and Traber, 1996;Soubeyran et al, 1999).…”