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Nucleophosmin saves the tumor suppressor Fbw7- (green) from cytoplasmic destruction by sequestering it in the nucleolus.

Bonetti et al. find that mutations in a nucleolar chaperone destroy a tumor suppressor and simultaneously activate an oncogene.

Mutations in the nucleolar chaperone nucleophosmin (NPM) are a major cause of acute myelogenous leukemia. One way NPM mutations cause cancer is by failing to sequester the tumor suppressor Arf in the nucleolus, thus allowing its degradation in the cytoplasm. Bonetti and colleagues now show that mutant NPM has the same effect on another protein called Fbw7-, which suppresses the oncogenic protein c-Myc.

Fbw7- ubiquitinates c-Myc and promotes its degradation, thus lowering the levels of this powerful transcription factor. In cells lacking functional NPM, the authors showed that Fbw7- partially relocalized to the cytoplasm and was degraded. As a consequence, the half-life of c-Myc doubled in NPM mutant-bearing cells, and the total amount of c-Myc rose. Cytoplasmic Fbw7- could not prevent c-Myc from promoting tumors in culture. This loss of Fbw7- regulation of c-Myc could be mitigated by blocking nuclear export.

Mutant NPM still bound to Fbw7-, but was unable to retain it in the nucleolus. The authors think that the chaperone activity of normal NPM ensures proper folding of its binding partners and helps prevent their degradation by retaining them in the nucleolus.

Bonetti, P., et al. 2008. J. Cell Biol. doi:10.1083/jcb.200711040.[Abstract/Free Full Text]

Richard Robinson

rrobinson{at}nasw.org

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This Article PDF (Full Text) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Robinson, R. PubMed Articles by Robinson, R. Social Bookmarking                      What's this?