Abstract
The down-regulation of DOC-2/DAB2 gene, which encodes a unique phosphoprotein modulating signal pathways elicited by exogenous stimuli, is often associated with several cancer types; however, the underlying mechanism is still unknown. Dramatically different expression levels of DOC-2/DAB2 mRNA and protein are observed among several human transitional cell carcinoma (TCC) cell lines, suggesting that transcriptional regulation may play a role in these cells. In this study, we have shown that the histone acetylation status associated with the 5' upstream regulatory sequence of DOC-2/DAB2 gene is one of the key determinants for its gene expression. In addition, GATA6 but not other GATA family members, such as GATA2 and GATA4, can specifically induce DOC-2/DAB2 promoter activity, although GATA transcription factors share a very similar DNA-binding sequence. We also show that increased histone acetylation and the presence of GATA6 have a synergistic effect on DOC-2/DAB2 promoter activity, which results in the elevation of DOC-2/DAB2 protein expression. Thus, we conclude that transcriptional regulation of DOC-2/DAB2 gene in human TCC is determined by histone acetylation and a specific transcription factor (i.e., GATA6), which underlie the reduced DOC-2/DAB2 protein expression in TCC cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylation
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport / biosynthesis
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Adaptor Proteins, Vesicular Transport / genetics*
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Apoptosis Regulatory Proteins
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Base Sequence
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Carcinoma, Transitional Cell / enzymology
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Carcinoma, Transitional Cell / genetics*
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Carcinoma, Transitional Cell / metabolism
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Cell Line, Tumor
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Chromatin / genetics
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Chromatin / metabolism
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Depsipeptides / pharmacology
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Down-Regulation
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GATA6 Transcription Factor
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Gene Expression Regulation, Neoplastic*
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Genes, Tumor Suppressor
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Genetic Vectors / genetics
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Histone Deacetylase Inhibitors*
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Histone Deacetylases / metabolism
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Histones / metabolism
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Humans
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Molecular Sequence Data
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Promoter Regions, Genetic
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Transcription Factors / biosynthesis
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transfection
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Tumor Suppressor Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Apoptosis Regulatory Proteins
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Chromatin
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DAB2 protein, human
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DNA-Binding Proteins
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Depsipeptides
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GATA6 Transcription Factor
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GATA6 protein, human
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Histone Deacetylase Inhibitors
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Histones
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Transcription Factors
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Tumor Suppressor Proteins
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romidepsin
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Histone Deacetylases