Inducible expression of RbAp46 activates c-Jun NH2-terminal kinase-dependent apoptosis and suppresses progressive growth of tumor xenografts in nude mice.
Inducible expression of RbAp46 activates c-Jun NH2-terminal kinase-dependent apoptosis and suppresses progressive growth of tumor xenografts in nude mice.
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发表时间：
2003-11
影响因子：
2
通讯作者：
Teng-fei Zhang;Shui-Qing Yu;B. Loggie;Zhaoyi Wang
中科院分区：
文献类型：
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作者：
Teng-fei Zhang;Shui-Qing Yu;B. Loggie;Zhaoyi Wang
视网膜母细胞瘤（Rb）抑制相关蛋白46（RbAp 46）是WD重复蛋白家族的成员，是组蛋白修饰和重塑复合物的组分。先前，我们证明RbAp 46抑制细胞生长并抑制肿瘤细胞系的转化表型。材料与方法我们在Saos-2细胞中建立了四环素诱导的RbAp 46表达系统，以测试RbAp 46诱导对体外细胞生长和体内肿瘤形成的影响。结果RbAp 46的诱导表达激活了c-Jun N-末端激酶（JNK）信号通路，诱导Saos-2细胞凋亡。JNK 1的显性负性突变体可以抑制RbAp 46诱导的JNK活性，阻断RbAp 46介导的细胞凋亡。我们还发现，诱导RbAp 46表达强烈抑制了裸鼠移植瘤的形成，并显著降低了已建立的肿瘤异种移植物的生长。结论RbAp 46通过JNK途径具有促凋亡活性，并能抑制移植瘤的生长。
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.