Rig-G Protein Links Retinoid and Interferon Signal Pathways To Inhibit Cell Cycle through Increased p27 and p21 Protein Levels.

Over the last two decades, the molecular mechanisms of all trans retinoic acid (ATRA)-induced differentiation of acute promyelocytic leukemia (APL) cells have been greatly explored The Rig-G gene was first isolated from an ATRA-treated APL cell line NB4. The expression of Rig-G was undetectable in untreated NB4 cells, but could be dramatically induced by ATRA treatment. Interestingly, database research showed that Rig-G represented a member of interferon-inducible (IFI) gene family. Moreover, a synergistic induction of Rig-G mRNA in NB4 cells by ATRA and interferons (IFNs) indicated a possible role of Rig-G in crosstalk between these two signaling pathways. In this work, we show that Rig-G is indeed a direct target of STAT1 protein, a critical transcription factor in regulating IFN responses, and involved in both ATRA and interferon pathways. By stable transfection of Rig-G in U937 cells, we find that Rig-G protein can significantly accumulate the cells at G1/S transition and inhibit cell proliferation through enhancing some important cell cycle regulators. Further studies demonstrate that Rig-G can physically interact with JAB1 (Jun activating domain binding protein). It can decrease JAB1-enhanced AP-1 transactivities through preventing JAB1 from entering the nucleus, and impair JAB1-dependent p27 nuclear export and degradation, resulting in a nuclear accumulation of p27. In addition, we show that Rig-G can also downregulate c-Myc followed by an upregulation of p21, another major negative player of cell growth. Taken together, it seems that Rig-G may be one of the first experimentally proven molecular mediators responsible for IFNs-dependent growth-suppressive responses, and it can link both IFN- and ATRA-triggered intracellular pathways to synergistically inhibit cell growth in many cell types.