Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7gamma

Mutations leading to aberrant cytoplasmic localization of Nucleophosmin (NPM) are the most frequent genetic alteration in acute myelogenous leukemia (AML). NPM is a nucleolar chaperone, which inhibits cell proliferation and possesses tumor suppressor functions in vitro and in vivo. NPM binds the Arf tumor suppressor and protects it from degradation. The AML-associated NPM mutant (NPMmut) also binds p19Arf, but is unable to protect it from degradation, suggesting that inactivation of p19Arfcontributes to leukemogenesis in AMLs. We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7γ, a component of the E3 ligase complex involved in the ubiquitination and proteasome-degradation of c-Myc. NPM was required for nucleolar localization and stabilization of Fbw7γ. As a consequence, c-Myc was stabilized in cells lacking NPM. Expression of NPMmut also led to c-Myc stabilization, due to its ability to interact with Fbw7γ and delocalize it to the cytoplasm, where it is degraded. Since Fbw7 induces degradation of other growth promoting proteins, the NPM-Fbw7 interaction emerges as a central tumor suppressor mechanism in human cancer.