IRF-9/STAT2 [corrected] functional interaction drives retinoic acid-induced gene G expression independently of STAT1.
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 IFNalpha 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 IFNalpha autocrine pathway, a finding that suggests a novel mechanism for the signal cross-talk between IFNalpha 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.
Lou
Ye-Jiang
YJ
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Pan
Xiao-Rong
XR
Jia
Pei-Min
PM
Li
Dong
D
Xiao
Shu
S
Zhang
Zhang-Lin
ZL
Chen
Sai-Juan
SJ
Chen
Zhu
Z
Tong
Jian-Hua
JH
D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology
C116468:IFIT3 protein, human; C494227:IRF9 protein, human; D050856:Interferon Regulatory Factor-1; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D014212:Tretinoin