Abstract
We have previously shown that interferon-gamma (IFN-gamma) inhibits expression of the metastasis-promoting protein S100A4. In the present study, we further explore the mechanism behind the IFN-gamma-mediated effects on the human S100A4 promoter and demonstrate that IFN-gamma represses S100A4 promoter activity through induction of the class II transactivator (CIITA). The acidic domain in the N-terminal part of CIITA was crucial for the observed IFN-gamma-induced inhibition of S100A4 promoter activity, probably by binding the histone acetyltransferase CBP/p300. Importantly, overexpression of CIITA significantly reduced the expression of endogenous S100A4. Our data suggest a model where CIITA represses S100A4 transcription through sequestering of CBP/p300, thereby reducing the level of CBP/p300 at the S100A4 promoter, which in turn leads to inhibition of S100A4 transcription.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Neoplasms / genetics
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology
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COS Cells
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Cell Line
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Cell Line, Tumor
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Chlorocebus aethiops
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DNA, Neoplasm / genetics
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Interferon-gamma / pharmacology*
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Nuclear Proteins / drug effects*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Osteosarcoma / genetics
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Osteosarcoma / metabolism
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Osteosarcoma / pathology
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / genetics
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S100 Calcium-Binding Protein A4
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S100 Proteins / drug effects*
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S100 Proteins / genetics
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S100 Proteins / metabolism
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Trans-Activators / drug effects*
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription, Genetic / drug effects*
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Transfection
Substances
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DNA, Neoplasm
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MHC class II transactivator protein
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Nuclear Proteins
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S100 Calcium-Binding Protein A4
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S100 Proteins
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Trans-Activators
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S100A4 protein, human
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Interferon-gamma