Retinoic acid is able to induce interferon regulatory factor 1 in squamous carcinoma cells via a STAT-1 independent signalling pathway.
Interferon regulatory factor 1 (IRF-1) transcription factor binds to DNA sequence elements found in the promoters of type I IFN and IFN-inducible genes. Transient up-regulation of the IRF-1 gene by virus and IFN treatment causes the consequent induction of many IFN-inducible genes involved in cell growth control and apoptosis. We reported recently that IFN-alpha and all-trans retinoic Acid (RA) inhibit the cell proliferation of squamous carcinoma cell line ME-180 by inducing apoptotic cell death. IRF-1 expression correlates with the IFN-alpha-induced apoptosis phenomenon and, surprisingly, with the RA-induced apoptosis phenomenon. To study how these two different ligands cross-talk in the regulation of cellular antitumor responses, the signalling pathways involved in IRF-1 induction were analyzed in RA and/or IFN-alpha-treated ME-180 cells. We provide evidence indicating that RA-induced IRF-1 gene expression is independent of the STAT-1 activation pathway, despite the presence of the IFN-gamma activated sequence element in the gene promoter, but involves nuclear factor-kappaB activation. Thus, here we first describe the activation of nuclear factor-kappaB by both IFN-alpha and RA in the ME-180 cell line. The induced IRF-1 protein is successively able to bind the IFN-stimulated responsive element in the promoter of the target gene 2',5'-oligoadenylate synthetase.
D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D003609:Dactinomycin / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D050856:Interferon Regulatory Factor-1; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology / Q000502:physiology*; D014407:Tumor Cells, Cultured