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Characterization of the Nuclear Import Pathways of Galectin-3

¹ Tumor Progression and Metastasis Program, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; ² Department of Otolaryngology and Sensory Organ Surgery, Osaka University Graduate School of Medicine, Osaka, Japan; and ³ Department of Urology, School of Medicine, University of Tokushima, Tokushima, Japan

Requests for reprints: Avraham Raz, Karmanos Cancer Institute, Wayne State University Medical School, 110 East Warren Avenue, Detroit, MI 48201. Phone: 313-833-0960; Fax: 313-831-7518; E-mail: raza{at}kci.wayne.edu.

Galectin-3 (Gal-3), a pleiotropic ß-galactoside–binding protein, was shown to be involved in several nuclear-dependent functions, including up-regulation of transcriptional factors, RNA processing, and cell cycle regulation. Gal-3 compartmentalization in the nucleus versus the cytoplasm affects, in part, the malignant phenotype of various cancers. However, to date, the mechanism by which Gal-3 translocates into the nucleus remains debatable. Thus, we have constructed and expressed a variety of fusion proteins containing deletion mutants of Gal-3 fused with monomers, dimers, and trimers of enhanced green fluorescent protein and searched for the Gal-3 sequence motifs essential for its nuclear localization in vivo. In addition, a digitonin-permeabilized, cell-free transport in vitro assay was used to directly examine the mechanism of Gal-3 nuclear import. Partial deletions of the COOH-terminal region (114-250) of the human Gal-3 significantly decreases its nuclear translocation, whereas a peptide (1-115) was transported to the nuclei. The in vitro nuclear import assay revealed that there are at least two independent nuclear pathways for shuttling Gal-3 into the nucleus: a passive diffusion and an active transport. This is the first article providing direct evidence for the nuclear import mechanisms of Gal-3 and suggests that Gal-3 nuclear translocation is governed by dual pathways, whereas the cytoplasmic/nuclear distribution may be regulated by multiple processes, including cytoplasmic anchorage, nuclear retention, and or nuclear export. These results may lead to the development of a therapeutic modality aiming at abrogating Gal-3 translocation into the nucleus and thus hampering its activity during cancer progression and metastasis. (Cancer Res 2006; 66(20): 9995-10006)

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