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J. Biol. Chem., Vol. 281, Issue 51, 39649-39659, December 22, 2006

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Importin-mediated Nuclear Translocation of Galectin-3^*

Susumu Nakahara, Victor Hogan, Hidenori Inohara, and Avraham Raz¹

From the Tumor Progression and Metastasis Program, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201 and the Department of Otolaryngology and Sensory Organ Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Galectin-3 (Gal-3), a member of a -galactoside-binding protein family, is involved in RNA processing and cell cycle regulation through activation of transcription factors when translocated to the nucleus. We have previously shown that Gal-3 can import into the nucleus through at least two pathways; via passive diffusion and/or active transport (Nakahara, S., Oka, N., Wang, Y., Hogan, V., Inohara, H, and Raz, A. (2006) Cancer Res. 66, 9995-10006). Here, we investigated the process mediated by the active nuclear transport of Gal-3 and have identified a nuclear localization signal (NLS)-like motif in its protein sequence, ²²³HRVKKL²²⁸, that resembles p53 and c-Myc NLSs (³⁷⁸SRHKKL³⁸³, ³²²AKRVKL³²⁷), respectively. Moreover, trimers of enhanced green fluorescence protein (3xGFP) fused with this NLS-like sequence, which is too large to passively diffuse through the nuclear pores, accumulated in the cell nuclei. To gain insights into this newly identified nuclear import mechanism, the interaction between Gal-3 and importins (importins and ) that carry the NLS harboring nuclear proteins into the nucleus, was investigated. Pull-down assays and bimolecular fluorescence complementation (BiFC) analysis revealed that wild-type Gal-3, but not mutant Gal-3 (R224A), binds to importin-. Down-regulation of importin- by RNA interference (RNAi) efficiently abrogates its nuclear accumulation. Furthermore, we provide evidence that impaired nuclear translocation of mutant Gal-3 protein (R224A) results in accelerated degradation compared with the wild-type protein. Thus, these results suggest that Gal-3 is translocated to the nucleus, in part, via the importin-/ route and that Arg²²⁴ amino acid residue of human Gal-3 is essential for its active nuclear translocation and its molecular stability.

Received for publication, August 22, 2006 , and in revised form, October 13, 2006.

^* This work was supported by Grant R37CA46120-19 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Tumor Progression and Metastasis Program, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201. Tel.: 313-833-0960; Fax: 313-831-7518; E-mail: raza{at}karmanos.org.

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