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

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

Carcinogenesis is contingent on cells acquiring resistance to intrinsic cell death mechanisms. 27 Resultant tumor growth is the balance between tumor cell growth rates and tumor cell death rates. Early studies of NMI mostly examined its characteristics in hematologic cells. However, a consistent functional role for NMI in hematologic malignancies has not been identified thus far. Nagel et al. discovered that the interaction between STAT5, NMI and N-myc mediates repression of myocyte enhancing factor 2c leading to increased apoptosis in T cell acute lymphoblastic leukemia. 28 Sun et al. identified NMI, from a human leukocyte library, as an interactor of the viral apoptosis-inducing protein, Apoptin. 29 Apoptin is encoded by the chicken anemia virus which infects hematopoietic cells in young chickens, and causes cell death that leads to anemia. 30 Interestingly, Apoptin was found to selectively induce apoptosis in tumorigenic cell lines but not in non-transformed, non-tumorigenic cells. 31 It was observed that Apoptin localized to the nucleus in malignant cells yet it remained cytoplasmic in non-transformed cells. The nuclear localization sequence (NLS) of Apoptin allows it to interact with the anaphase-promoting complex/cyclosome, causing G2/M cell cycle arrest and apoptosis. 32 The region of Apoptin that interacts with NMI was later confirmed as a nuclear export sequence. Taken together, these data support a potential mechanism by which NMI-Apoptin interaction selectively diminishes nuclear export of Apoptin and subsequently enhances the apoptic activity of Apoptin in transformed cells. This mechanism is speculative, especially since the nature of the NMI-Apoptin interaction is not well understood; yet these data do provide suggestive evidence of NMI being involved in cancer-cell-specific apoptosis.