Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-xL
Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-xL
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DOI：
10.1016/j.yexcr.2004.04.031
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发表时间：
2004-08-15
影响因子：
3.7
通讯作者：
Tao, WF
中科院分区：
文献类型：
--
作者：
Ke, HN;Pei, J;Tao, WF
Lats 2，也称为Kpm，是新的Lats肿瘤抑制基因家族的第二个哺乳动物成员。最近的研究表明，Lats 2通过控制G1/S和/或G2/M转换负调控细胞周期。为了进一步了解Lats 2在控制人类癌症发展中的作用，我们通过转导表达人Lats 2的复制缺陷型腺病毒（Ad-Lats 2）在人肺癌细胞中表达了该蛋白。使用各种技术，包括膜联蛋白V摄取，切割PARP，和DNA梯状，我们已经证明，异位表达的人Lats 2诱导两个肺癌细胞系，A549和H1299的凋亡。半胱天冬酶-3，7，8和9在Ad-Lats 2转导的细胞中被加工;然而，启动半胱天冬酶级联反应的是活性半胱天冬酶-9，而不是半胱天冬酶-8。caspase-3和9特异性抑制剂延迟Lats 2介导的细胞凋亡的发生。Western blot分析显示，抗凋亡蛋白BCL-2和BCL-x（L）在Ad-Lats 2转导的人肺癌细胞中下调，但促凋亡蛋白BAX没有下调。Bcl-2或Bcl-x（L）在这些细胞中的过表达导致Lats 2介导的半胱天冬酶切割和凋亡的抑制。这些结果表明，Lats 2通过下调人肺癌细胞中的抗凋亡蛋白BCL-2和BCL-x（L）诱导凋亡。(C)2004年爱思唯尔公司All rights reserved.
Lats2, also known as Kpm, is the second mammalian member of the novel Lats tumor suppressor gene family. Recent studies have demonstrated that Lats2 negatively regulates the cell cycle by controlling G1/S and/or G2/M transition. To further understand the role of Lats2 in the control of human cancer development, we have expressed the protein in human lung cancer cells by transduction of a replication-deficient adenovirus expressing human Lats2 (Ad-Lats2). Using a variety of techniques, including Annexin V uptake, cleavage of PARP, and DNA laddering, we have demonstrated that the ectopic expression of human Lats2 induced apoptosis in two lung cancer cell lines, A549 and H1299. Caspases-3, 7, 8, and 9 were processed in the Ad-Lats2-transduced cells; however, it was active caspase-9, not caspase-8, that initiated the caspase cascade. Inhibitors specific to caspase-3 and 9 delayed the onset of Lats2-mediated apoptosis. Western blot analysis revealed that antiapoptotic proteins, BCL-2 and BCL-x(L), but not the pro-apoptotic protein, BAX, were downregulated in Ad-Lats2-transduced human lung cancer cells. Overexpression of either Bcl-2 or Bcl-x(L) in these cells lead to the suppression of Lats2-mediated caspase cleavage and apoptosis. These results show that Lats2 induces apoptosis through downregulating anti-apoptotic proteins, BCL-2 and BCL-x(L), in human lung cancer cells. (C) 2004 Elsevier Inc. All rights reserved.