Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis.
Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis.
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DOI：
10.1083/jcb.200703040
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发表时间：
2007-11-19
期刊：
影响因子：
--
通讯作者：
Daniel PT
中科院分区：
文献类型：
--
作者：
Gillissen B;Essmann F;Hemmati PG;Richter A;Richter A;Oztop I;Chinnadurai G;Dörken B;Daniel PT
B细胞淋巴瘤2(Bcl2)同源结构域3(BH3)是Bcl2家族中唯一的蛋白，它将细胞死亡信号与Bax和/或Bak的激活联系起来。仅BH3蛋白NBK/Bik通过Bax依赖/Bak非依赖的机制诱导细胞死亡。相反，短剪接变异体Bclx诱导的细胞死亡依赖于Bak，而不是Bax。这表明Bak功能正常，但无法被NBK激活。在这里，我们发现髓系白血病细胞白血病1(Mcl-1)与Bak的结合在NBK表达后持续存在，并抑制NBK诱导的Bax缺陷细胞的凋亡。相反，仅有BH3的Puma蛋白破坏了Mcl-1-Bak的相互作用，并通过Bax和Bak触发细胞死亡。靶向敲除Mcl-1克服了对Bak的抑制，并允许NBK激活Bak。因此，NBK被Mcl-1抑制，Mcl-1干扰Bak的激活。不同的仅BH3蛋白依赖于Bax和/或Bak，这一发现对靶向Bc l-2的抗癌药物的设计具有重要的意义。
B cell lymphoma 2 (Bcl-2) homology domain 3 (BH3)–only proteins of the Bcl-2 family are important functional adaptors that link cell death signals to the activation of Bax and/or Bak. The BH3-only protein Nbk/Bik induces cell death via an entirely Bax-dependent/Bak-independent mechanism. In contrast, cell death induced by the short splice variant of Bcl-x depends on Bak but not Bax. This indicates that Bak is functional but fails to become activated by Nbk. Here, we show that binding of myeloid cell leukemia 1 (Mcl-1) to Bak persists after Nbk expression and inhibits Nbk-induced apoptosis in Bax-deficient cells. In contrast, the BH3-only protein Puma disrupts Mcl-1–Bak interaction and triggers cell death via both Bax and Bak. Targeted knockdown of Mcl-1 overcomes inhibition of Bak and allows for Bak activation by Nbk. Thus, Nbk is held in check by Mcl-1 that interferes with activation of Bak. The finding that different BH3-only proteins rely specifically on Bax, Bak, or both has important implications for the design of anticancer drugs targeting Bcl-2.
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影响因子：
11.4
作者：
Germain, M;Mathai, JP;Shore, GC
通讯作者：
Shore, GC
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Shore, GC
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作者：
Germain, M;Mathai, JP;Shore, GC
通讯作者：
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