UV induces nucleolar translocation of ING1 through two distinct nucleolar targeting sequences

The ING1 candidate tumor suppressor is downregulated in a variety of primar y tumors and established cancer cell lines. Blocking its expression experim entally promotes unregulated growth in vitro and in vivo, using cell and an imal models. Alternative splicing products encode proteins that localize to the nucleus, inhibit cell cycle progression and affect apoptosis in differ ent model systems. Here we show that ING1 proteins translocate to the nucle olus 12-48 h after UV-induced DNA damage, When a small 50 amino acid portio n of ING1 was fused to green fluorescent protein, the fusion protein was ef ficiently targeted to the nucleolus, indicating that ING1 possesses an intr insic nucleolar targeting sequence (NTS). We mapped this activity to two di stinct 4 amino acid regions, which individually direct fused heterologous p roteins to the nucleolus. Overexpression of ING1 induced apoptosis of prima ry fibroblasts in the presence and absence of UV exposure. In contrast, NTS mutants of ING1 that were not targeted to the nucleolus did not efficientl y induce apoptosis when overexpressed and instead protected cells from UV-i nduced apoptosis, Taken together, these results indicate that UV induces IN G1 to translocate to the nucleolus and that this translocation may facilita te apoptosis.