title: Class II major histocompatibility complex transactivator (CIITA) inhibits matrix metalloproteinase-9 gene expression.
abstract: Matrix metalloproteinases (MMPs) are a family of structurally related proteins with the collective capability to degrade all components of the extracellular matrix. Although MMP-mediated degradation of the extracellular matrix occurs physiologically, numerous pathological conditions exhibit increased MMP levels and excessive matrix degradation. Previous work from our laboratory has shown that interferon-gamma inhibits MMP-9 expression in a manner dependent upon STAT-1alpha. Here we extend our previous observations and show that the class II major histocompatibility complex transactivator (CIITA), a transcriptional target of STAT-1alpha, is also capable of inhibiting MMP-9 expression. By using stable cell lines that inducibly express CIITA or various mutant forms of CIITA, we show that CIITA requires the ability to bind the CREB-binding protein (CBP) to effectively inhibit MMP-9 expression. Furthermore, we show that CIITA-mediated inhibition of the MMP-9 gene does not rely on the transcriptional capability of CIITA. These findings support a model wherein CIITA inhibits MMP-9 expression by binding to and sequestering CBP, which reduces the levels of CBP at the MMP-9 promoter, inhibits levels of acetylated histone 3 at the MMP-9 promoter, and subsequently inhibits MMP-9 expression.
authors.affiliation: Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0005, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Nozell
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Ma
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wilson
authors.forename: Reesha
authors.initials: R
authors.lastname: Shah
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D002843:Chromatin / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D005802:Genes, MHC Class II; D006801:Humans; D015151:Immunoblotting; D008285:Major Histocompatibility Complex; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002843:Chromatin; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D012260:Ribonucleases; D020780:Matrix Metalloproteinase 9