RUNX3 cooperates with FoxO3a to induce apoptosis in gastric cancer cells
RUNX3 cooperates with FoxO3a to induce apoptosis in gastric cancer cells
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DOI：
10.1074/jbc.m512151200
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发表时间：
2006-02-24
影响因子：
4.8
通讯作者：
Ito, Y
中科院分区：
文献类型：
--
作者：
Yamamura, Y;Lee, WL;Ito, Y
转录因子RUNX3介导胃上皮细胞的凋亡和生长抑制，是一种在胃癌细胞中经常缺失的候选抑癌基因。在这里，我们发现在不表达RUNX3的细胞系中恢复RUNX3的表达可以诱导细胞凋亡，并且它与Forkhead转录因子FOXO3a/FKHRL1物理上相互作用，已知FOXO3a/FKHRL1是细胞凋亡和细胞周期的重要调节因子。活性非磷酸化FOXO3a/FKHRL1在胃癌细胞系中有表达。RUNX3诱导的细胞凋亡依赖于Bim的表达，而Bim的表达需要RUNX3和FOXO3a/FKHRL1共同作用。此外，我们还发现RUNX3与FOXO3a/FKHRL1的相互作用对Bim的表达和小鼠胚胎成纤维细胞的凋亡也是不可或缺的。在Bim启动子中，RUNX3与两个保守的RUNX结合元件(Rbe1和RBE2)结合，Rbe1紧接在FoxO结合元件的下游。RUNX3和FOXO3a/FKHRL1在Bim启动子上的物理相互作用激活了Bim的转录。这些结果表明，RUNX3与FOXO3a/FKHRL1协同作用，通过激活Bim参与诱导细胞凋亡，可能在胃癌的抑瘤作用中发挥重要作用。
The transcription factor RUNX3, which mediates apoptosis and cell growth inhibition in gastric epithelial cells, is a candidate tumor suppressor that is frequently lost in gastric cancer cells. Here, we found that restoration of RUNX3 expression in the cell line not expressing RUNX3 induced apoptosis and that it physically interacted with the Forkhead transcription factor FoxO3a/FKHRL1, known to be an important regulator of apoptosis and the cell cycle. Active unphosphorylated FoxO3a/FKHRL1 was expressed in the gastric cancer cell lines. RUNX3-induced apoptosis depended on the expression of Bim, a proapoptotic BH3-only protein, and both RUNX3 and FoxO3a/FKHRL1 were required for induction of Bim expression. Furthermore, we showed that interaction of RUNX3 and FoxO3a/FKHRL1 was also indispensable for Bim expression and apoptosis in mouse embryonic fibroblasts. In the Bim promoter, RUNX3 bound to two conserved RUNX-binding elements (RBE1 and RBE2), with RBE1 being immediately downstream of a FoxO-binding element. The physical interaction of RUNX3 and FoxO3a/FKHRL1 on the Bim promoter activated transcription of Bim. These findings show that RUNX3 cooperates with FoxO3a/FKHRL1 to participate in the induction of apoptosis by activating Bim and may play an important role in tumor suppression in gastric cancer.