Lactase-phlorizin hydrolase is a brush-border enzyme which is specifically expressed in the small intestine where it hydrolyses lactose, the main carbohydrate found in milk. We have previously demonstrated in transgenic mice that the tissue-specific and developmental expression of lactase is controlled by a 1 kb upstream region of the pig lactase gene. Two homeodomain transcription factors, caudal-related homeodomain protein (Cdx2) and hepatic nuclear factor 1α (HNF1α), are known to bind to regulatory cis elements in the promoters for several intestine-specific genes, including lactase, and are present in mammalian intestinal epithelia from an early stage in development. In the present study, we examined whether Cdx2 and HNF1α physically interact and co-operatively activate transcription from the lactase-phlorizin hydrolase promoter. We show that the presence of both factors leads to a much higher level of transcription than the sum of the activation by either factor alone. The N-terminal activation domain of Cdx2 is required for maximal synergy with HNF1α. With the use of pull-down assays, we demonstrate a direct protein-protein interaction between Cdx2 and HNF1α. The interaction domain includes the homeodomain region of both proteins. This is the first demonstration of a functional interaction between two transcription factors involved in the activation of a number of intestine-specific genes. Synergistic interaction between tissue-restricted factors is likely to be an important mechanism for reinforcing developmental and tissue-specific gene expression within the intestine.
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Research Article|
February 22 2000
Interaction between the homeodomain proteins Cdx2 and HNF1α mediates expression of the lactase-phlorizin hydrolase gene
Cathy MITCHELMORE;
Cathy MITCHELMORE
1
1To whom correspondence should be addressed (e-mail mitch@;imbg.ku.dk).
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Jesper T. TROELSEN;
Jesper T. TROELSEN
1Department of Medical Biochemistry and Genetics, Biochemical Laboratory C, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Nikolaj SPODSBERG;
Nikolaj SPODSBERG
1Department of Medical Biochemistry and Genetics, Biochemical Laboratory C, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Hans SJÖSTRÖM;
Hans SJÖSTRÖM
1Department of Medical Biochemistry and Genetics, Biochemical Laboratory C, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Ove NORÉN
Ove NORÉN
1Department of Medical Biochemistry and Genetics, Biochemical Laboratory C, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Publisher: Portland Press Ltd
Received:
July 15 1999
Revision Received:
November 17 1999
Accepted:
December 14 1999
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 346 (2): 529–535.
Article history
Received:
July 15 1999
Revision Received:
November 17 1999
Accepted:
December 14 1999
Citation
Cathy MITCHELMORE, Jesper T. TROELSEN, Nikolaj SPODSBERG, Hans SJÖSTRÖM, Ove NORÉN; Interaction between the homeodomain proteins Cdx2 and HNF1α mediates expression of the lactase-phlorizin hydrolase gene. Biochem J 1 March 2000; 346 (2): 529–535. doi: https://doi.org/10.1042/bj3460529
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