title: IRF1 Downregulation by Ras/MEK Is Independent of Translational Control of IRF1 mRNA.
abstract: Oncogenic activation of Ras/MEK downregulates the expression of interferon regulatory factor 1 (IRF1), which is a prerequisite for oncolytic viruses to replicate in cancer cells [1]. Moreover, restoration of IRF1 expression is essential to induce apoptosis of cancer cells treated with a MEK inhibitor [2]. However, the molecular mechanisms that underlie IRF1 downregulation by Ras/MEK remain unclear. In this study, we determined whether Ras/MEK activation modulates IRF1 expression at its translational level. MEK inhibition increased the activity of IRF1 promoter construct in Ras transformed NIH3T3 cells and wild type MEF, but not in IRF1 deficient MEF, indicating that IRF1 protein is required for the transcriptional activation of IRF1. By conducting reporter analysis using IRF1 5'- and 3'- UTR constructs, we determined that cis elements on 5'- and 3'-UTR of IRF1 mRNA are not involved in the IRF1 regulation by Ras/MEK. We further compared the recruitment of ribosomes to IRF1 mRNA in RasV12 cells treated with or without the MEK inhibitor by conducting polysome analysis. No difference was observed in the polysomal distribution of IRF1 mRNA between RasV12 cells treated with and without the MEK inhibitor. These results suggest that regulation of IRF1 translation is independent of IRF1 downregulation by Ras/MEK.
authors: Division of BioMedical Science, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Dr., St. John's, NL, A1B 3V6, Canada.
authors: Yumiko
authors: Y
authors: Komatsu
authors: Division of BioMedical Science, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Dr., St. John's, NL, A1B 3V6, Canada.
authors: Leena
authors: L
authors: Derwish
authors: Division of BioMedical Science, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Dr., St. John's, NL, A1B 3V6, Canada.
authors: Kensuke
authors: http://orcid.org/0000-0002-3812-9825
authors: K
authors: Hirasawa
mesh_terms: D000818:Animals; D015536:Down-Regulation; D017930:Genes, Reporter; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050856:Interferon Regulatory Factor-1; D012333:RNA, Messenger; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins