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Signaling and Regulation

MDM2 Splice Variants Predominantly Localize to the Nucleoplasm Mediated by a COOH-Terminal Nuclear Localization Signal

¹ Department of Molecular Pharmacology, St. Jude Children's Research Hospital, and ² Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee

Requests for reprints: Linda C. Harris, St. Jude Children's Research Hospital, 332 N Lauderdale St, Mail Stop 230, TN 38105. Phone: 901-495-3833; Fax: 901-495-4293. E-mail: Linda.Harris{at}stjude.org

Of the >40 alternative and aberrant splice variants of MDM2 that have been described to date, the majority has lost both the well-characterized nuclear localization signal (NLS1) and the nuclear export signal (NES) sequence. Because cellular localization of proteins provides insight regarding their potential function, we determined the localization of three different MDM2 splice variants. The splice variants chosen were the common variants MDM2-A and MDM2-B. In addition, MDM2-FB26 was chosen because it is one of the few variants described that contains the complete p53-binding site. All three splice variants predominantly localized to the nucleus. Nuclear localization of MDM2-A and MDM2-B was controlled by a previously uncharacterized nuclear localization signal (NLS2), whereas nucleoplasmic localization of MDM2-FB26 was mediated by NLS1. p53 and full-length MDM2 colocalized with the splice variants in the nucleus. MDM2-A and MDM2-B both contain a COOH-terminal RING finger domain, and interaction with full-length MDM2 through this domain was confirmed. MDM2-FB26 was the only splice variant evaluated that contained a p53-binding domain; however, interaction between MDM2-FB26 and p53 could not be shown. p14^ARF did not colocalize with the splice variants and was predominantly expressed within the nucleoli. In summary, nuclear localization signals responsible for the nucleoplasmic distribution of MDM2 splice variants have been characterized. Colocalization and interaction of MDM2-A and MDM2-B with full-length MDM2 in the nucleus have important physiologic consequences, for example, deregulation of p53 activity. (Mol Cancer Res 2007;5(4):403–12)