Analysis of the regulation of the A33 antigen gene reveals intestine-specific mechanisms of gene expression.
The A33 antigen is a transmembrane protein expressed almost exclusively by intestinal epithelial cells. The level of its expression is robust and uniform throughout the rostrocaudal axis of the human and mouse intestines. In the colon, strong expression is found in the basolateral membranes of both the proliferating cells in the lower regions of the crypts and the differentiating cells in the upper regions of crypts. Similarly, in the small intestine, the protein is highly expressed by all the epithelial cells in the crypts and by the differentiated cells migrating over the villi. Thus, the A33 antigen has emerged as a definitive marker for all intestinal epithelial cells, irrespective of cell lineage and differentiation status. To understand the molecular mechanisms mediating this rare tissue-specific expression pattern, we undertook a comprehensive analysis of the 5'-regulatory region of the human A33 antigen gene. This allowed us to point to positive cis-regulatory elements incorporating consensus Krüppel-like factor and caudal-related homeobox (CDX)-binding sites, located just upstream from the human A33 antigen transcription start site, as being important for the intestine-specific expression pattern of this gene. Further analysis provided evidence that the A33 antigen gene may be one of only a few target genes to be described thus far for the intestine-specific homeobox transcription factor, CDX1. Taken together, our data lead us to propose that the activity of CDX1 is pivotal in mediating the exquisite, intestine-specific expression pattern of the A33 antigen gene.
Ludwig Institute for Cancer Research, Melbourne Branch, Post Office Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
Cameron N
CN
Johnstone
Sara J
SJ
White
Niall C
NC
Tebbutt
Fiona J
FJ
Clay
Matthias
M
Ernst
William H
WH
Biggs
Carrie S
CS
Viars
Suzanne
S
Czekay
Karen C
KC
Arden
Joan K
JK
Heath
D024506:5' Flanking Region; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D015179:Colorectal Neoplasms / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C104258:GPA33 protein, human; C504395:Gpa33 protein, mouse; D008562:Membrane Glycoproteins