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Cell Growth & Differentiation Vol. 10, 263-270, April 1999
© 1999 American Association for Cancer Research

Retinoic Acid Is Able to Induce Interferon Regulatory Factor 1 in Squamous Carcinoma Cells via a STAT-1 Independent Signalling Pathway1

Zulema A. Percario, Valeria Giandomenico, Gianna Fiorucci, Maria V. Chiantore, Serena Vannucchi, John Hiscott, Elisabetta Affabris and Giovanna Romeo2

Laboratory of Virology, Istituto Superiore di Sanità [G. F., M. V. C., S. V., E. A., G. R.], and Istituto Tecnologie Biomediche [G. F., M. V. C., G. R.], Consiglio Nazionale delle Ricerche, 00161 Rome, Italy; Department of Biology, University of Rome 3, 00146 Rome, Italy [Z. A. P., V. G., E. A.]; and Lady Davis Institute, McGill University, Molecular Oncology Group, Montreal H3T 1E2, Canada [J. H.]

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-{kappa}B activation. Thus, here we first describe the activation of nuclear factor-{kappa}B 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.




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Copyright © 1999 by the American Association of Cancer Research.