The Myc-nucleophosmin-ARF network: a complex web unveiled.

The multifunctional nucleolar proteins, nucleophosmin (NPM) and the tumor suppressor ARF, have been assigned numerous roles in diverse cellular processes impacting cellular proliferation, tumorigenesis and apoptosis. In addition, both proteins have been linked to the oncogenic function of c-Myc, a transcription factor that drives the majority of human cancers. Both proteins are induced by oncogenic c-Myc, but have opposing outcomes. Whereas loss of ARF accelerates c-Myc-induced tumorigenesis, NPM overexpression enhances c-Myc transformation. Accordingly, ARF expression is lost in many tumors, while NPM expression is elevated. Previously, we demonstrated that ARF interacts directly with c-Myc, leading to inhibition of its transforming activity while enhancing its apoptotic activity, independently of p53. We have recently shown that NPM also binds directly to c-Myc, but with opposite effects compared to ARF. NPM dramatically enhances the oncogenic activity of c-Myc, independently of ARF and p53. In tumor cells, the ARF-p53 pathway is often inactivated while NPM is elevated. However, when NPM and ARF are both expressed with oncogenic c-Myc the outcome of the interactions becomes more complex, since NPM and ARF also interact directly and NPM controls ARF localization. In this report we demonstrate that in the presence of ARF, NPM overexpression dramatically inhibits c-Myc-induced p53-independent apoptosis, while enhancing proliferation and transformation. We find that NPM sequesters ARF in nucleoli, blocking the relocalization of ARF to the nucleoplasm caused by activation of c-Myc. Therefore, the fate of a cell to undergo apoptosis or become transformed is dependent on this complex interacting network of oncogenic and tumor suppressor proteins.