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In Vivo Analysis of Importin Proteins Reveals Cellular Proliferation Inhibition and Substrate Specificity

Medical Faculty of the Charité, The Franz Volhard Clinic, HELIOS Klinikum-Berlin, and The Max Delbrueck Center for Molecular Medicine,¹ Department of Biology, Chemistry, and Pharmaceutics, Free University of Berlin, Berlin,² Institute of Biology, University of Lübeck, Lübeck, Germany³

Received 30 March 2004/ Returned for modification 7 May 2004/ Accepted 9 September 2004

The "classical" nuclear import pathway depends on importins and ß. Humans have only one importin ß, while six importins have been described. Whether or not distinct importins are essential for specific import pathways in living human cells is unclear. We used RNA interference technology to specifically down-regulate the expression of ubiquitously expressed human importins in HeLa cells. Down-regulation of importins 3, 5, 7, and ß strongly inhibited HeLa cell proliferation, while down-regulation of importins 1 and 4 had only a minor effect or no effect. Nucleoplasmin import was not prevented by down-regulation of any importin, indicating that the importin /ß pathway was generally not affected. In contrast, importin 3 or 5 down-regulation specifically inhibited the nuclear import of the Ran guanine nucleotide exchange factor, RCC1. Coinjection of recombinant importins and RCC1 into down-regulated cells demonstrated that these transport defects were specifically caused by the limited availability of importin 3 in both cases. Thus, importin 3 is the only importin responsible for the classical nuclear import of RCC1 in living cells.

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