The tumor suppressor WARTS activates the Omi/HtrA2-dependent pathway of cell death
The tumor suppressor WARTS activates the Omi/HtrA2-dependent pathway of cell death
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DOI：
10.1038/sj.onc.1208682
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发表时间：
2005-08-11
期刊：
影响因子：
8
通讯作者：
Saya, H
中科院分区：
文献类型：
--
作者：
Kuninaka, S;Nomura, M;Saya, H
果蝇肿瘤抑制因子WARTS（Wts）是一种进化上保守的丝氨酸/苏氨酸激酶，参与调节增殖和凋亡的信号复合物，以确保果蝇的适当大小和形状。已经发现这种复合物的人类对应物在癌症中经常下调或突变。WATS是Wts的人类同源物，也被称为肿瘤抑制因子和有丝分裂调节因子，但其在肿瘤发生中的分子意义仍然不清楚。在这里，我们表明，WARTS通过其C-末端结合到PDZ结构域的促凋亡丝氨酸蛋白酶Omi/HtrA 2。WARTS的耗竭抑制Omi/HtrA 2介导的细胞死亡，而WARTS的过表达促进了这一过程。此外，WARTS在体内和体外都可以增强Omi/HtrA 2的蛋白酶活性。因此，Omi/HtrA 2介导的细胞死亡的激活是WARTS的肿瘤抑制活性的潜在机制。
Drosophila tumor suppressor WARTS (Wts) is an evolutionally conserved serine/threonine kinase and participates in a signaling complex that regulates both proliferation and apoptosis to ensure the proper size and shape of the fly. Human counterparts of this complex have been found to be frequently downregulated or mutated in cancers. WARTS, a human homolog of Wts, is also known as tumor suppressor and mitotic regulator, but its molecular implications in tumorigenesis are still obscure. Here, we show that WARTS binds via its C-terminus to the PDZ domain of a proapoptotic serine protease Omi/HtrA2. Depletion of WARTS inhibited Omi/HtrA2-mediated cell death, whereas overexpression of WARTS promoted this process. Furthermore, WARTS can enhance the protease activity of Omi/HtrA2 both in vivo and in vitro. Activation of Omi/HtrA2-mediated cell death is thus a potential mechanism for the tumor suppressive activity of WARTS.