Myeloid Leukemia-Associated Nucleophosmin Mutants Perturb p53-Dependent and Independent Activities of the Arf Tumor Suppressor Protein

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Abstract
Nucleophosmin (NPM or B23) plays key roles in ribosome biogenesis, centrosome dupli-cation, and maintenance of genomic integrity. Mutations affecting the carboxylterminal domain of NPM occur in a significant percentage of adult patients with acute myeloid leukemia (AML), and these alterations create an additional nuclear export signal that relocalizes much of the protein from its normal nucleolar stores to the cytoplasm. When induced by oncogenic stress, the Arf tumor suppressor protein accumulates within the nucleolus, where it is physically associated with, and stabilized by, NPM. Ectopic overexpression of an NPM cytoplasmic mutant (NPMc) relocalized p19Arf and the endogenous NPM protein to the cytoplasm. NPMc-dependent export of p19Arf from the nucleus inhibited its functional interaction with the p53 negative regulator, Mdm2, and blunted Arf-induced activation of the p53 transcriptional program. Cytoplasmic NPM relocalization also attenuated Arf-induced sumoylation of Mdm2 and NPM and prevented wild t...

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