Inducible Expression of RbAp46 Activates c-Jun NH2-terminal Kinase-dependent Apoptosis and Suppresses Progressive Growth of Tumor Xenografts in Nude Mice

Background: The retinoblastoma (Rb) suppressor-associated protein 46 (RbAp46) is a member of the WD-repeat protein family and a component of histone modifying and remodeling complexes. Previously, we demonstrated that RbAp46 inhibits cell growth and suppresses the transformed phenotypes of tumor cell lines. Materials and Methods: We established a tetracycline-inducible RbAp46 expression system in Saos-2 cells to test the effects of RbAp46 induction on cell growth in vitro and on tumor formation in vivo. Results: We found that inducible expression of RbAp46 activated the c-Jun N-terminal kinase (JNK) signaling pathway and triggered apoptosis in Saos-2 cells. A dominant-negative mutant of JNK1, which can inhibit RbAp46-induced JNK activity, blocked RbAp46-mediated apoptosis. We also found that the induction of RbAp46 expression strongly suppressed the formation of tumors grafted in nude mice and drastically reduced growth of established tumor xenografts. Conclusion: These results revealed a novel proapoptotic activity for RbAp46 via the JNK pathway and demonstrated that induction of RbAp46 expression inhibits progressive growth of tumor grafts in vivo.