Current Biology
Volume 10, Issue 9, 1 May 2000, Pages 539-542
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Brief Communication
Contribution of two independent MDM2-binding domains in p14ARF to p53 stabilization

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Abstract

The MDM2 protein targets the p53 tumor suppressor for ubiquitin-dependent degradation [1], and can function both as an E3 ubiquitin ligase [2] and as a regulator of the subcellular localization of p53 [3]. Oncogene activation stabilizes p53 through expression of the ARF protein (p14ARF in humans, p19ARF in the mouse) [4], and loss of ARF allows tumor development without loss of wild-type p53 5, 6. ARF binds directly to MDM2, and prevents MDM2 from targeting p53 for degradation 6, 7, 8, 9 by inhibiting the E3 ligase activity of MDM2 [2] and preventing nuclear export of MDM2 and p53 10, 11. Interaction between ARF and MDM2 results in the localization of both proteins to the nucleolus 12, 13, 14 through nucleolar localization signals (NoLS) in ARF and MDM2 11, 12, 13, 14. Here, we report a new NoLS within the highly conserved amino-terminal 22 amino acids of p14ARF, a region that we found could interact with MDM2, relocalize MDM2 to the nucleolus and inhibit the ability of MDM2 to degrade p53. In contrast, the carboxy-terminal fragment of p14ARF, which contains the previously described NoLS [11], did not drive nucleolar localization of MDM2, although this region could bind MDM2 and weakly inhibit its ability to degrade p53. Our results support the importance of nucleolar sequestration for the efficient inactivation of MDM2. The inhibition of MDM2 by a small peptide from the amino terminus of p14ARF might be exploited to restore p53 function in tumors.

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1

Present address: Institute of Molecular Medicine, Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany.