The ARF tumor suppressor is widely regarded as a major upstream activator of p53 in response to hyperproliferative signals. However, the emergence of a second, p53-independent ARF pathway has altered the way we think about ARF tumor surveillance. Specifically, animal models have provided genetic evidence of an alternative ARF pathway. Mice lacking ARF and p53 exhibit a more profound tumor spectrum when compared to single-null ARF or p53 littermates and eye defects observed in ARF or ARF/p53-null animals are not seen in p53-null mice. Recent experiments have further demonstrated that ARF can induce cell growth arrest in the presence of mutant p53, or in the absence of p53 and Mdm2 altogether. Our long-term objective is to understand the mechanisms underlying ARF's p53-independent properties. In search of p53-independent ARF targets, we isolated a novel ARF binding protein, nucleophosmin (NPM). NPM is a component of the centrosome and is also a critical phospho-substrate for cyclin E-CDK2 during progression into S phase. In this manner, phospho-NPM serves as a key regulator of centrosome duplication. We have found that the ARF-NPM complex is restricted to the nucleolus, preventing NPM localization to the centrosome where it normally serves as a substrate for cyclin E-CDK2 holoenzymes. Furthermore, ARF prevents the direct phosphorylation of NPM by active cyclin Ecdk2 complexes, inhibiting subsequent centrosome duplication. Re-introduction of Mdm2 reverses the p53-independent properties of ARF: NPM re-localizes to the centrosome, centrosomes duplicate, and S phase progression ensues. We hypothesize that ARF, through active recruitment of NPM into the nucleolus away from cyclin E-cdk2 complexes, can function as a p53-independent cell cycle brake, inhibiting the basic process of centrosome duplication. ? ?
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