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Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7

¹ Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
² Dipartimento di Medicina, Chirurgia e Odontoiatria, University of Milano, 20122 Milan, Italy
³ The FIRC Institute of Molecular Oncology Foundation (IFOM), 20139 Milan, Italy

Correspondence to Emanuela Colombo: emanuela.colombo{at}ifom-ieo-campus.it; or Pier G. Pelicci: piergiuseppe.pelicci{at}ifom-ieo-campus.it

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 Fbw7, 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 Fbw7. 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 Fbw7 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.

Abbreviations used in this paper: AML, acute myelogenous leukemia; ChIP, chromatin immunoprecipitation; CHX, cycloheximide; LMB, leptomycin B; MEF, mouse embryonic fibroblast; Myc-ER, Myc–estrogen receptor fusion protein; NPM, nucleophosmin; NPMmut, NPM mutant; OHT, hydroxytamoxifen; QPCR, quantitative PCR; WB, Western blot; WT, wild type.

© 2008 Bonetti et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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