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]
IFN-induced protein with tetratricopeptide repeats 2 (IFIT2), one of the most highly responsive interferon-stimulated genes, inhibits the proliferation and migration of cancer cells and regulates viral replication. IFIT2 has been demonstrated to be a cytoskeleton-associated protein that becomes enriched in the mitotic spindle of cells. However, the molecular mechanisms by which IFIT2 executes biological functions are largely unclear. The findings of this study showed that inhibiting the activation of proteasome led to the enrichment of IFIT2 and induced the aggregation of IFIT2 protein in the centrosome. Microtubule inhibitor colchicine and dynein inhibitor ciliobrevin inhibited the proteasome inhibitor-induced aggregation of IFIT2 protein in the centrosome. Intriguingly, IFIT2 and proteasome inhibitor worked together to induce the apoptosis of cancer cells. The results of the present study revealed that the inhibition of proteasome activity blocked the degradation of IFIT2 and promoted the aggregation of IFIT2 in the centrosome, which in turn induced cell apoptosis. In short, IFIT2 may be a potential target for cancer therapeutics.
of detection) did not identify an aberrant clonal plasma cell population in this patient.We conclude that for select patients with clinical features of systemic AL amyloidosis (ie, heart failure with preserved ejection fraction, proteinuria, unexplained hepatomegaly, and axonal demyelinating peripheral neuropathy), the absence of monoclonal gammopathy should not deter aspiration of subcutaneous fat and/or tissue biopsy of the affected organ. Only histopathological analysis for Congophilia and accurate precursor protein typing can lead to diagnosis in some cases. Moreover, it is important to distinguish these systemic cases from localized AL amyloidosis, which does not require systemic chemotherapy.The authors declare no competing conflicts of interest.
AUTHOR CONTRIBUTIONSAS collected and analyzed data, and wrote the manuscript in consultation with YK, DJM and JMS; VS edited and revised the final version.
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