Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

CDX1 is a transcription factor that plays a key role in intestinal development and differentiation. However, the downstream targets of CDX1 are less well defined than those of its close homologue, CDX2. We report here the identification of downstream targets of CDX1 using microarray gene-expression...

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Vydáno v:	Proceedings of the National Academy of Sciences - PNAS Ročník 106; číslo 6; s. 1936
Hlavní autoři:	Chan, Carol W M, Wong, Newton A, Liu, Ying, Bicknell, David, Turley, Helen, Hollins, Laura, Miller, Crispin J, Wilding, Jennifer L, Bodmer, Walter F
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 10.02.2009
Témata:	Binding Sites Cell Line, Tumor Colorectal Neoplasms - etiology Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology Gastrointestinal Tract Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes, Homeobox - physiology Homeodomain Proteins - genetics Homeodomain Proteins - physiology Humans Keratin-20 - genetics Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic
ISSN:	1091-6490, 1091-6490
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Abstract	CDX1 is a transcription factor that plays a key role in intestinal development and differentiation. However, the downstream targets of CDX1 are less well defined than those of its close homologue, CDX2. We report here the identification of downstream targets of CDX1 using microarray gene-expression analysis and other approaches. Keratin 20 (KRT20), a member of the intermediate filament and a well-known marker of intestinal differentiation, was initially identified as one of the genes likely to be directly regulated by CDX1. CDX1 and KRT20 mRNA expression were significantly correlated in a panel of 38 colorectal cancer cell lines. Deletion and mutation analysis of the KRT20 promoter showed that the minimum regulatory region for the control of KRT20 expression by CDX1 is within 246 bp upstream of the KRT20 transcription start site. ChIP analysis confirmed that CDX1 binds to the predicted CDX elements in this region of the KRT20 promoter in vivo. In addition, immunohistochemistry showed expression of CDX1 parallels that of KRT20 in the normal crypt, which further supports their close relationship. In summary, our observations strongly imply that KRT20 is directly regulated by CDX1, and therefore suggest a role for CDX1 in maintaining differentiation in intestinal epithelial cells. Because a key feature of the development of a cancer is an unbalanced program of proliferation and differentiation, dysregulation of CDX1 may be an advantage for the development of a colorectal carcinoma. This could, therefore, explain the relatively frequent down regulation of CDX1 in colorectal carcinomas by hypermethylation.
AbstractList	CDX1 is a transcription factor that plays a key role in intestinal development and differentiation. However, the downstream targets of CDX1 are less well defined than those of its close homologue, CDX2. We report here the identification of downstream targets of CDX1 using microarray gene-expression analysis and other approaches. Keratin 20 (KRT20), a member of the intermediate filament and a well-known marker of intestinal differentiation, was initially identified as one of the genes likely to be directly regulated by CDX1. CDX1 and KRT20 mRNA expression were significantly correlated in a panel of 38 colorectal cancer cell lines. Deletion and mutation analysis of the KRT20 promoter showed that the minimum regulatory region for the control of KRT20 expression by CDX1 is within 246 bp upstream of the KRT20 transcription start site. ChIP analysis confirmed that CDX1 binds to the predicted CDX elements in this region of the KRT20 promoter in vivo. In addition, immunohistochemistry showed expression of CDX1 parallels that of KRT20 in the normal crypt, which further supports their close relationship. In summary, our observations strongly imply that KRT20 is directly regulated by CDX1, and therefore suggest a role for CDX1 in maintaining differentiation in intestinal epithelial cells. Because a key feature of the development of a cancer is an unbalanced program of proliferation and differentiation, dysregulation of CDX1 may be an advantage for the development of a colorectal carcinoma. This could, therefore, explain the relatively frequent down regulation of CDX1 in colorectal carcinomas by hypermethylation. CDX1 is a transcription factor that plays a key role in intestinal development and differentiation. However, the downstream targets of CDX1 are less well defined than those of its close homologue, CDX2. We report here the identification of downstream targets of CDX1 using microarray gene-expression analysis and other approaches. Keratin 20 (KRT20), a member of the intermediate filament and a well-known marker of intestinal differentiation, was initially identified as one of the genes likely to be directly regulated by CDX1. CDX1 and KRT20 mRNA expression were significantly correlated in a panel of 38 colorectal cancer cell lines. Deletion and mutation analysis of the KRT20 promoter showed that the minimum regulatory region for the control of KRT20 expression by CDX1 is within 246 bp upstream of the KRT20 transcription start site. ChIP analysis confirmed that CDX1 binds to the predicted CDX elements in this region of the KRT20 promoter in vivo. In addition, immunohistochemistry showed expression of CDX1 parallels that of KRT20 in the normal crypt, which further supports their close relationship. In summary, our observations strongly imply that KRT20 is directly regulated by CDX1, and therefore suggest a role for CDX1 in maintaining differentiation in intestinal epithelial cells. Because a key feature of the development of a cancer is an unbalanced program of proliferation and differentiation, dysregulation of CDX1 may be an advantage for the development of a colorectal carcinoma. This could, therefore, explain the relatively frequent down regulation of CDX1 in colorectal carcinomas by hypermethylation.CDX1 is a transcription factor that plays a key role in intestinal development and differentiation. However, the downstream targets of CDX1 are less well defined than those of its close homologue, CDX2. We report here the identification of downstream targets of CDX1 using microarray gene-expression analysis and other approaches. Keratin 20 (KRT20), a member of the intermediate filament and a well-known marker of intestinal differentiation, was initially identified as one of the genes likely to be directly regulated by CDX1. CDX1 and KRT20 mRNA expression were significantly correlated in a panel of 38 colorectal cancer cell lines. Deletion and mutation analysis of the KRT20 promoter showed that the minimum regulatory region for the control of KRT20 expression by CDX1 is within 246 bp upstream of the KRT20 transcription start site. ChIP analysis confirmed that CDX1 binds to the predicted CDX elements in this region of the KRT20 promoter in vivo. In addition, immunohistochemistry showed expression of CDX1 parallels that of KRT20 in the normal crypt, which further supports their close relationship. In summary, our observations strongly imply that KRT20 is directly regulated by CDX1, and therefore suggest a role for CDX1 in maintaining differentiation in intestinal epithelial cells. Because a key feature of the development of a cancer is an unbalanced program of proliferation and differentiation, dysregulation of CDX1 may be an advantage for the development of a colorectal carcinoma. This could, therefore, explain the relatively frequent down regulation of CDX1 in colorectal carcinomas by hypermethylation.
Author	Bicknell, David Liu, Ying Hollins, Laura Chan, Carol W M Turley, Helen Wong, Newton A Miller, Crispin J Wilding, Jennifer L Bodmer, Walter F
Author_xml	– sequence: 1 givenname: Carol W M surname: Chan fullname: Chan, Carol W M organization: Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS, United Kingdom – sequence: 2 givenname: Newton A surname: Wong fullname: Wong, Newton A – sequence: 3 givenname: Ying surname: Liu fullname: Liu, Ying – sequence: 4 givenname: David surname: Bicknell fullname: Bicknell, David – sequence: 5 givenname: Helen surname: Turley fullname: Turley, Helen – sequence: 6 givenname: Laura surname: Hollins fullname: Hollins, Laura – sequence: 7 givenname: Crispin J surname: Miller fullname: Miller, Crispin J – sequence: 8 givenname: Jennifer L surname: Wilding fullname: Wilding, Jennifer L – sequence: 9 givenname: Walter F surname: Bodmer fullname: Bodmer, Walter F
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Snippet	CDX1 is a transcription factor that plays a key role in intestinal development and differentiation. However, the downstream targets of CDX1 are less well...
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SubjectTerms	Binding Sites Cell Line, Tumor Colorectal Neoplasms - etiology Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology Gastrointestinal Tract Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes, Homeobox - physiology Homeodomain Proteins - genetics Homeodomain Proteins - physiology Humans Keratin-20 - genetics Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic
Title	Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1
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