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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 (p14^ARF in humans, p19^ARF 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 [6–9] 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 [12–14] through nucleolar localization signals (NoLS) in ARF and MDM2 [11–14]. Here, we report a new NoLS within the highly conserved amino-terminal 22 amino acids of p14^ARF, a region that we found could interact with MDM2 …