Oct-1 maintains an intermediate, stable state of HLA-DRA promoter repression in Rb-defective cells: an Oct-1-containing repressosome that prevents NF-Y binding to the HLA-DRA promoter.
The cell surface HLA-DR molecule binds foreign peptide antigen and forms an intercellular complex with the T cell receptor in the course of the development of an immune response against or immune tolerance to the antigen represented by the bound peptide. The HLA-DR molecule also functions as a receptor that mediates cell signaling pathways, including as yet poorly characterized pathway(s) leading to apoptosis. Expression of HLA-DR mRNA and protein is ordinarily inducible by interferon-gamma but is not inducible in tumor cells defective for the retinoblastoma tumor suppressor protein (Rb). In the case of the HLA-DRA gene, which encodes the HLA-DR heavy chain, previous work has indicated that this loss of inducibility is attributable to Oct-1 binding to the HLA-DRA promoter. In this report, we used Oct-1 antisense transformants to determine that Oct-1 represses the interferon-gamma response of the endogenous HLA-DRA gene. This determination is consistent with results from a chromatin immunoprecipitation assay, indicating that Oct-1 occupies the endogenous HLA-DRA promoter when the HLA-DRA promoter is inactive in Rb-defective cells but not when the promoter is converted to a previously defined, transcriptionally competent state, induced by treatment of the Rb-defective cells with the HDAC inhibitor, trichostatin A. In vitro DNA-protein binding analyses indicated that Oct-1 prevents HLA-DRA promoter activation by mediating the formation of a complex of proteins, termed DRAN (DRA negative), that blocks NF-Y access to the promoter.
Osborne
Aaron R
AR
Department of Biochemistry, College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Zhang
Hongquan
H
Fejer
Gyorgy
G
Palubin
Kimberly M
KM
Niesen
Melissa I
MI
Blanck
George
G
D001665:Binding Sites; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006684:HLA-DR Antigens / Q000235:genetics* / Q000378:metabolism*; D059805:HLA-DR alpha-Chains; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D051863:Host Cell Factor C1; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D046911:Macromolecular Substances; D008285:Major Histocompatibility Complex; D050811:Octamer Transcription Factor-1; D020320:Oligoribonucleotides, Antisense / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D023081:CCAAT-Binding Factor; D002843:Chromatin; D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D056572:Histone Deacetylase Inhibitors; D051863:Host Cell Factor C1; D046911:Macromolecular Substances; D050811:Octamer Transcription Factor-1; D020320:Oligoribonucleotides, Antisense; C494165:POU2F1 protein, human; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D007371:Interferon-gamma; D006655:Histone Deacetylases