Deregulated expression of interferon regulatory factor-1 in oncogene-transformed mouse fibroblasts.
Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that has been historically associated with type I IFN activation and antioncogenic properties. We studied IRF-1 expression and DNA-binding capacity in nontransformed and transformed mouse fibroblasts. A 43-kDa nuclear IRF-1 protein was expressed biphasically during the cell cycle in primary mouse embryo fibroblasts, nontransformed NIH 3T3 cells, and ras revertants. IRF-1 expression became constitutive in ras-transformed NIH 3T3 cells and in cells transformed by oncogenes ets, fes, fos, her-2/neu, met, mos, raf, or trk, suggesting that deregulated IRF-1 expression may be associated with loss of growth control. Lysyl oxidase (LO), a ras suppressor that is downregulated in ras transformants, is an IRF-1 target gene, but it is not stimulated by abundant IRF-1 present in transformants, while another IRF-1 target gene (iNOS) is transcribed. IRF-1 from either normal or ras-transformed cells bound to IRF elements in the IFN-beta and LO promoters. IRF-1 in transformants can, therefore, bind to but not transactivate the LO promoter, and the presence of IRF-1 is not sufficient to suppress ras transformation. LO expression may effect the regulated expression of IRF-1: a ras revertant, which was generated by stable transfection of LO cDNA, regained the normal biphasic IRF-1 pattern. A mainly cytoplasmic, constitutively expressed 46-kDa protein with immunologic identity to the 43-kDa nuclear IRF-1 was also present in normal and transformed cells, but as it did not bind to the IRF elements, its function is unclear.
Contente
Sara
S
United States Military Cancer Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. scontente@usuhs.mil
Attard
Frank A
FA
Yeh
Tze-Jou Annie
TJ
Buchhagen
Dorothy L
DL
Friedman
Robert M
RM
D016475:3T3 Cells; D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta / Q000235:genetics; D051379:Mice; D009857:Oncogenes; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D016899:Interferon-beta; D004247:DNA; D008249:Protein-Lysine 6-Oxidase