Intestinal epithelia cells express unique gene products which enable the intestine to perform specialized tasks including the absorption and processing of nutrients. Enterocyte function varies during development, along the length of the intestinal tract (horizontal axis), along the crypt-villus unit (vertical axis), in response to physiological stimuli, and in disease states. This complex pattern of function is directly related, in many cases, to the pattern of expression of intestine-specific genes that encode proteins which perform those functions. Little is known about the molecular mechanisms which regulate patterns of intestine- specific gene transcription or intestinal epithelial cell development and differentiation. In this proposal, sucrase-isomaltase (SI) will be used as a model gene to probe the molecular mechanisms which regulate enterocyte- specific gene transcription. SI has been chosen because it is enterocyte- specific, expressed at moderately high levels, has a complex pattern of developmental and adult expression, is altered in physiological and disease states, and is expressed in intestinal tumor cell lines which enables in vitro experimental approaches. The reagents required for these studies have been developed including human and mouse SI CDNAS and genomic clones containing the 5'-flanking regions of both the human and mouse SI genes. Transfection experiments have demonstrated that the human SI gene contains elements capable of directing intestine-specific transcription an transgenic mice containing a human SI gene construct have been made. Therefore, the goals of this proposal are: 1) To identify DNA regulatory regions in the SI gene and the corresponding sequence-specific nuclear binding proteins which are necessary to direct efficient, enterocyte- specific transcription, and 2) To determine which DNA regulatory regions are required to recapitulate the spatial (horizontal and vertical) and developmental patterns of SI gene expression in adult tissues using transgenic mice. The experiments outlined in this proposal use a multifaceted approach to provide detailed information on the regulation of SI gene transcription. Elucidation of transcriptional mechanisms for tissue-specific genes in other tissues has led to identification of DNA binding proteins which direct cell-specific transcription and are important for cellular differentiation and proliferation. Thus, SI DNA elements and/or nuclear binding proteins may participate in the regulation of multiple intestinal genes, in the process of differentiation and development, or serve to regulate proliferation. The anticipated result of these studies will be a better understanding of the molecular mechanisms which regulate intestinal gene expression, development, and differentiation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Xiao, Fang; Crissey, Mary Ann S; Lynch, John P et al. (2005) Intestinal metaplasia with a high salt diet induces epithelial proliferation and alters cell composition in the gastric mucosa of mice. Cancer Biol Ther 4:669-75
Rankin, Erinn B; Xu, Wei; Silberg, Debra G et al. (2004) Putative intestine-specific enhancers located in 5' sequence of the CDX1 gene regulate CDX1 expression in the intestine. Am J Physiol Gastrointest Liver Physiol 286:G872-80
Suh, Eun Ran; Ha, Chong S; Rankin, Erinn B et al. (2002) DNA methylation down-regulates CDX1 gene expression in colorectal cancer cell lines. J Biol Chem 277:35795-800
Boudreau, Francois; Rings, Edmond H H M; Swain, Gary P et al. (2002) A novel colonic repressor element regulates intestinal gene expression by interacting with Cux/CDP. Mol Cell Biol 22:5467-78
Boudreau, Francois; Rings, Edmond H H M; van Wering, Herbert M et al. (2002) Hepatocyte nuclear factor-1 alpha, GATA-4, and caudal related homeodomain protein Cdx2 interact functionally to modulate intestinal gene transcription. Implication for the developmental regulation of the sucrase-isomaltase gene. J Biol Chem 277:31909-17
Boudreau, F; Zhu, Y; Traber, P G (2001) Sucrase-isomaltase gene transcription requires the hepatocyte nuclear factor-1 (HNF-1) regulatory element and is regulated by the ratio of HNF-1 alpha to HNF-1 beta. J Biol Chem 276:32122-8
Rings, E H; Boudreau, F; Taylor, J K et al. (2001) Phosphorylation of the serine 60 residue within the Cdx2 activation domain mediates its transactivation capacity. Gastroenterology 121:1437-50
Suh, E; Wang, Z; Swain, G P et al. (2001) Clusterin gene transcription is activated by caudal-related homeobox genes in intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 280:G149-56
Lorentz, O; Suh, E R; Taylor, J K et al. (1999) CREB-binding [corrected] protein interacts with the homeodomain protein Cdx2 and enhances transcriptional activity. J Biol Chem 274:7196-9
Taylor, J K; Levy, T; Suh, E R et al. (1997) Activation of enhancer elements by the homeobox gene Cdx2 is cell line specific. Nucleic Acids Res 25:2293-300

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