Retinoic Acid Exerts Dual Regulatory Actions on the Expression and Nuclear Localization of Interferon Regulatory Factor-1

Interferon regulatory factor-1 (IRF-1), a transcription factor and tumor suppressor involved in cell growth regulation and immune responses, has been shown to be induced by all-trans retinoic acid (ATRA). However, the factors controlling the cellular location and activity of IRF-1 are not well understood. In this study, we examined the expression of IRF-1 and its nuclear localization, DNA-binding activity, and target gene expression in human mammary epithelial MCF10A cells, a model of breast epithelial cell differentiation and carcinogenesis. Following initial treatment with ATRA, IRF-1 mRNA and protein were induced within 2 hrs, reached a peak (>30-fold induction) at 8 hrs, and declined afterwards. IRF-1 protein was predominantly cytoplasmic during this treatment. Although a second dose of ATRA or Am580 (a related retinoid selective for retinoic acid receptor-α [RARα]), given 16 hrs after the first dose, restimulated IRF-1 mRNA and protein levels to a similar level to that obtained by the first dose, IRF-1 was predominantly concentrated in the nucleus after restimulation. ATRA and Am580 also increased nuclear RARα, whereas retinoid X receptor-α (RXRa)—a dimerization partner for RARα, was localized to the nucleus upon second exposure to ATRA. However, ATRA and Am580 did not regulate the expression or activation of signal transducer and activator of transcription-1 (STAT-1), a transcription factor capable of inducing the expression of IRF-1, indicating an STAT-1–independent mechanism of regulation by ATRA and Am580. The increase in nuclear IRF-1 after retinoid restimulation was accompanied by enhanced binding to an IRF-E DNA response element, and elevated expression of an IRF-1 target gene, 2′,5′-oligoadenylate synthetase-2. The dual effect of retinoids in increasing IRF-1 mRNA and protein and in augmenting the nuclear localization of IRF-1 protein may be essential for maximizing the tumor suppressor activity and the immunosurveillance functions of IRF-1 in breast epithelial cells.

[1]  J. Russo,et al.  Estradiol and its metabolites 4‐hydroxyestradiol and 2‐hydroxyestradiol induce mutations in human breast epithelial cells , 2006, International journal of cancer.

[2]  Rebecca M. Williams,et al.  Nuclear Import of the Retinoid X Receptor, the Vitamin D Receptor, and Their Mutual Heterodimer* , 2005, Journal of Biological Chemistry.

[3]  Xin M. Luo,et al.  Physiological and Receptor-selective Retinoids Modulate Interferon γ Signaling by Increasing the Expression, Nuclear Localization, and Functional Activity of Interferon Regulatory Factor-1* , 2005, Journal of Biological Chemistry.

[4]  T. Giordano,et al.  Interferon regulatory factor 1 (IRF-1) and IRF-2 expression in breast cancer tissue microarrays. , 2005, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[5]  Robert Clarke,et al.  Interferon regulatory factor-1 (IRF-1) exhibits tumor suppressor activities in breast cancer associated with caspase activation and induction of apoptosis. , 2005, Carcinogenesis.

[6]  H. Kagechika,et al.  Synthetic retinoids: recent developments concerning structure and clinical utility. , 2005, Journal of medicinal chemistry.

[7]  P. Johnston,et al.  The 2,5 oligoadenylate synthetase/RNaseL pathway is a novel effector of BRCA1- and interferon-γ-mediated apoptosis , 2005, Oncogene.

[8]  J. Hiscott,et al.  A CRM1-dependent Nuclear Export Pathway Is Involved in the Regulation of IRF-5 Subcellular Localization* , 2005, Journal of Biological Chemistry.

[9]  R. Silverman,et al.  HPC1/RNASEL Mediates Apoptosis of Prostate Cancer Cells Treated with 2′,5′-Oligoadenylates, Topoisomerase I Inhibitors, and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand , 2004, Cancer Research.

[10]  Qiao Wu,et al.  RXRα acts as a carrier for TR3 nuclear export in a 9-cis retinoic acid-dependent manner in gastric cancer cells , 2004, Journal of Cell Science.

[11]  Vincent Laudet,et al.  Principles for modulation of the nuclear receptor superfamily , 2004, Nature Reviews Drug Discovery.

[12]  Xinjian Peng,et al.  Breast cancer progression in MCF10A series of cell lines is associated with alterations in retinoic acid and retinoid X receptors and with differential response to retinoids. , 2004, International journal of oncology.

[13]  Li-Na Wei.  Retinoids and receptor interacting protein 140 (RIP140) in gene regulation. , 2004, Current medicinal chemistry.

[14]  M. Privalsky,et al.  The role of corepressors in transcriptional regulation by nuclear hormone receptors. , 2004, Annual review of physiology.

[15]  J. Hiscott,et al.  A role for casein kinase II phosphorylation in the regulation of IRF-1 transcriptional activity , 2004, Molecular and Cellular Biochemistry.

[16]  G. Doherty,et al.  Localization of IFN-γ-Activated Stat1 and IFN Regulatory Factors 1 and 2 in Breast Cancer Cells , 2003 .

[17]  P. Pitha,et al.  Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. , 2003, Cancer research.

[18]  G. Doherty,et al.  Localization of IFN-gamma-activated Stat1 and IFN regulatory factors 1 and 2 in breast cancer cells. , 2003, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[19]  Yifan Ma,et al.  Opposing cytokine‐specific effects of all trans‐retinoic acid on the activation and expression of signal transducer and activator of transcription (STAT)‐1 in THP‐1 cells , 2002, Immunology.

[20]  I. Arany,et al.  Suppression of Growth by All-trans Retinoic Acid Requires Prolonged Induction of Interferon Regulatory Factor 1 in Cervical Squamous Carcinoma (SiHa) Cells , 2002, Clinical and Vaccine Immunology.

[21]  R. Lockey,et al.  2′-5′ Oligoadenylate Synthetase Plays a Critical Role in Interferon-γ Inhibition of Respiratory Syncytial Virus Infection of Human Epithelial Cells* , 2002, The Journal of Biological Chemistry.

[22]  Hansjörg Hauser,et al.  Review: Activities of IRF-1 , 2002 .

[23]  Hansjörg Hauser,et al.  Activities of IRF-1. , 2002, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[24]  G. Romeo,et al.  IRF-1 as a negative regulator of cell proliferation. , 2002, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[25]  L. Yu-Lee.  Prolactin modulation of immune and inflammatory responses. , 2002, Recent progress in hormone research.

[26]  Lucia Altucci,et al.  The promise of retinoids to fight against cancer , 2001, Nature Reviews Cancer.

[27]  T. Taniguchi,et al.  IRF family of transcription factors as regulators of host defense. , 2001, Annual review of immunology.

[28]  Kevin M. McBride,et al.  Regulated Nuclear-Cytoplasmic Localization of Interferon Regulatory Factor 3, a Subunit of Double-Stranded RNA-Activated Factor 1 , 2000, Molecular and Cellular Biology.

[29]  T. Taniguchi,et al.  The interferon regulatory factors and oncogenesis. , 2000, Seminars in cancer biology.

[30]  J. Hiscott,et al.  Retinoic acid is able to induce interferon regulatory factor 1 in squamous carcinoma cells via a STAT-1 independent signalling pathway. , 1999, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[31]  U. Kutay,et al.  Transport between the cell nucleus and the cytoplasm. , 1999, Annual review of cell and developmental biology.

[32]  F. Schaper,et al.  Functional domains of interferon regulatory factor I (IRF-1). , 1998, The Biochemical journal.

[33]  T. Taniguchi,et al.  The role of interferon regulatory factors in the interferon system and cell growth control. , 1998, Biochimie.

[34]  P. Rotwein,et al.  Growth hormone stimulates interferon regulatory factor-1 gene expression in the liver. , 1998, Endocrinology.

[35]  C. Schindler,et al.  Retinoic acid enhances the expression of interferon-induced proteins: evidence for multiple mechanisms of action , 1997, Oncogene.

[36]  Minoru Yoshida,et al.  CRM1 Is an Export Receptor for Leucine-Rich Nuclear Export Signals , 1997, Cell.

[37]  R. Pine,et al.  Retinoic acid activates interferon regulatory factor-1 gene expression in myeloid cells. , 1996, Blood.

[38]  A. Ross,et al.  Vitamin A and retinoids in antiviral responses , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  D. Hill,et al.  Retinyl methyl ether: binding to transport proteins and effect on transcriptional regulation. , 1996, Biochemical and biophysical research communications.

[40]  T. Barbui,et al.  AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells. , 1996, Blood.

[41]  N. Reich,et al.  Receptor to nucleus signaling by prolactin and interleukin 2 via activation of latent DNA-binding factors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[42]  T. Mak,et al.  Involvement of the IRF-1 transcription factor in antiviral responses to interferons. , 1994, Science.

[43]  T. Taniguchi,et al.  Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1 , 1994, Cell.

[44]  P Chambon,et al.  Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[45]  B. Shroot,et al.  Selective synthetic ligands for human nuclear retinoic acid receptors. , 1992, Skin pharmacology : the official journal of the Skin Pharmacology Society.

[46]  T. Taniguchi,et al.  Activation of IFN-beta element by IRF-1 requires a posttranslational event in addition to IRF-1 synthesis. , 1991, Nucleic acids research.

[47]  J. Russo,et al.  Ultrastructural and immunocytochemical characterization of an immortalized human breast epithelial cell line, MCF-10. , 1990, Cancer research.

[48]  J. Russo,et al.  Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. , 1990, Cancer research.

[49]  L. Yu-Lee,et al.  Interferon-regulatory factor 1 is an immediate-early gene under transcriptional regulation by prolactin in Nb2 T cells , 1990, Molecular and cellular biology.

[50]  T. Taniguchi,et al.  Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-β gene regulatory elements , 1988, Cell.