Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma.
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 Fbw7gamma, 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 Fbw7gamma. 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 Fbw7gamma 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.
Bonetti
Paola
P
Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy.
Davoli
Teresa
T
Sironi
Cristina
C
Amati
Bruno
B
Pelicci
Pier Giuseppe
PG
Colombo
Emanuela
E
D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D013816:Thermodynamics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D050505:Mutant Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D000090243:Nucleophosmin; D044767:Ubiquitin-Protein Ligases