Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7γ

Paola Bonetti, Teresa Davoli, Cristina Sironi, Bruno Amati, Pier Giuseppe Pelicci, Emanuela Colombo

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations leading to aberrant cytoplasmic localization of nucleophosmin (NPM) are the most frequent genetic alteration in acute myelogenous leukemia (AML). 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, which suggests that inactivation of p19Arf contributes 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 because of its ability to interact with Fbw7γ and delocalize it to the cytoplasm, where it is degraded. Because Fbw7 induces degradation of other growth-promoting proteins, the NPM-Fbw7 interaction emerges as a central tumor suppressor mechanism in human cancer.

Original languageEnglish
Pages (from-to)19-26
Number of pages8
JournalJournal of Cell Biology
Volume182
Issue number1
DOIs
Publication statusPublished - Jul 14 2008

ASJC Scopus subject areas

  • Cell Biology

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