Abstract
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.
Quiescent, Slow-Cycling Stem Cell Populations in Cancer: A Review of the Evidence and Discussion of Significance
