Roles of N-Myc and STAT interactor in cancer: From initiation to dissemination

Pruitt, Hawley C.; Devine, Daniel J.; Samant, Rajeev S.

Restoring or inhibiting NMI expression based on the specific cancer type may be an attractive therapeutic option in the future. Therefore, it is essential to know what pathways directly regulate the transcription, translation, and stability of NMI. Early studies of NMI induction indicate that its subcellular localization may be coupled to its regulation and function. Seminal studies identified that NMI expression is transcriptionally induced downstream of inflammatory cytokines, such as IFNg, IFNa and IL-2. 65 Downstream mediators such as STAT1 and STAT5 are most likely responsible for binding the NMI promoter. NMI, in turn, facilitates the activity of STATs, as previously described, allowing for a robust positive feedback response after cytokine stimulation. Interferon treatment resulted in the formation of high molecular mass complexes (HMMCs) of 300-400 kDa. These complexes were visualized as NMI/IFP35 speckles (NIS) in previous publications and they formed following dephosphorylation of IFP35. 75, 76 The function of the NIS complex warrants further exploration, as it may play a role in the human viral response. Other interactors of NMI such as c-Myc, Nmyc and c-fos are not thought to be contained in the HMMC. Molecular analysis confirmed that the fractionation properties of NMI change after treatment with IFNg, indicating a shift in subcellular location. 77 Multiple groups have shown that induction of NMI leads to its translocation into the nucleus. 77, 78 This may allow NMI to interact with nuclear transcription factors. It has also been reported that cytokineinduced NMI expression leads to reorganization of the NMI protein into puncta within the cytoplasm. 76 Thus, NMI seems to have a distinct cytoplasmic role(s).