Interferon-gamma-induced suppression of S100A4 transcription is mediated by the class II transactivator.
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.
Boye
Kjetil
K
Department of Tumor Biology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway. kjetil.boye@medisin.uio.no
Andersen
Kristin
K
Tveito
Siri
S
Øyjord
Tove
T
Maelandsmo
Gunhild M
GM
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
D004273:DNA, Neoplasm; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D015534:Trans-Activators; C077591:S100A4 protein, human; D007371:Interferon-gamma