Induction of apoptosis by NORE1A in a manner dependent on its nuclear export

The RASSF family proteins were identified as tumor suppressors in a variety of human cancers, and evidenced distinct subcellular localization patterns among their subfamilies and isoforms. In this study, we showed that NORE1A was exported actively via its nuclear export signal (NES) in the C-terminus (residues 372-379). Substitutions of three lysine residues of NORE1A NES to alanines (L372, 376, 379A) showed its localization to the dot structures of the nucleus, which was similar to the NORE1A localizations observed after the administration to cells of Leptomycin B, a nuclear export inhibitor. The NORE1A NES mutant inhibited caspase-mediated apoptosis, whereas wild-type NORE1A induced caspase-3 activation. Furthermore, the NORE1A NES mutant did not co-localize with GFP-MST1, the direct downstream target of NORE1A. These results show that the nuclear export of NORE1A via NES is involved in the NORE1A-mediated induction of apoptosis.