Interferon-γ-Induced Suppression of S100A4 Transcription Is Mediated by the Class II Transactivator

We have previously shown that interferon-γ (IFN-γ) inhibits expression of the metastasis-promoting protein S100A4. In the present study, we further explore the mechanism behind the IFN-γ-mediated effects on the human S100A4 promoter and demonstrate that IFN-γ 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-γ-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.

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