IFR-9/STAT2 Functional Interaction Drives Retinoic Acid–Induced Gene G Expression Independently of STAT1

Abstract

Retinoic acid-induced gene G (RIG-G), a gene originally identified in all-trans retinoic acid-treated NB4 acute promyelocytic leukemia cells, is also induced by IFNA in various hematopoietic and solid tumor cells. Our previous work showed that RIG-G possessed a potent antiproliferative activity. However, the mechanism for the transcriptional regulation of RIG-G gene remains unknown. Here, we report that signal transducer and activator of transcription (STAT) 2 together with IFN regulatory factor (IRF)-9 can effectively drive the transcription of RIG-G gene by their functional interaction through a STAT1-independent manner, even without the tyrosine phosphorylation of STAT2. The complex IRF-9/STAT2 is both necessary and sufficient for RIG-G gene expression. In addition, IRF-1 is also able to induce RIG-G gene expression through an IRF-9/STAT2-dependent or IRF-9/ STAT2-independent mechanism. Moreover, the induction of RIG-G by retinoic acid in NB4 cells resulted, to some extent, from an IFNA autocrine pathway, a finding that suggests a novel mechanism for the signal cross-talk between IFNA and retinoic acid. Taken together, our results provide for the first time the evidence of the biological significance of IRF-9/STAT2 complex, and furnish an alternative pathway modulating the expression of IFN-stimulated genes, contributing to the diversity of IFN signaling to mediate their multiple biological properties in normal and tumor cells. [Cancer Res 2009;69(8):3673-80]

Expression regulation of zebrafish interferon regulatory factor 9 by promoter analysis

“…However, there is still an overlapping set of genes induced by both types of IFNs (Sanda et al, 2006), reflecting the complexity of regulatory sequences of ISGs. Consistently, some ISGs can be induced by non-canonic JAK-STAT signaling pathway under IFN treatments (Fink et al, 2013;Lou et al, 2009;Rani et al, 2010).…”

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

“…The possibility that the STAT2/IRF9 complex binds to a yet uncharacterized consensus-responsive element would explain the failure of the previous bioinformatic strategy aimed at identifying TFs acting downstream of IFNβ and TNFα, as it was based on the databases of known DNA-binding consensus sites [11]. It is noteworthy to mention that alltrans retinoic acid (ATRA) was reported to stimulate the STAT2/IRF9-dependent induction of RIG-G gene expression [25]. Interestingly, ATRA was shown to be a potent inducer of DUOX2 in AECs [26].…”

Chromatin Dynamics of Gene Activation and Repression in Response to Interferon α (IFNα) Reveal New Roles for Phosphorylated and Unphosphorylated Forms of the Transcription Factor STAT2

“…Similarly, un-phosphory- lated STAT1 has been recently found to drive the constitutive expression of some target genes and to prolong the expression of specific ISGs without phosphorylation (56). Finally, Lou et al (57) have shown that STAT2-IRF9 heterodimers can drive the activation of RIG-G, a "typical" ISG, without requiring STAT2 phosphorylation. Thus, different STATs or P-STATs complexes could alternate each other on specific targets and exert both distinct and overlapping functions.…”