Apoptosis induced by cytoskeletal disruption requires distinct domains of MEKK1.
Apoptosis induced by cytoskeletal disruption requires distinct domains of MEKK1.
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DOI：
10.1371/journal.pone.0017310
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发表时间：
2011-02-25
期刊：
影响因子：
3.7
通讯作者：
Cheng G
中科院分区：
文献类型：
--
作者：
Tricker E;Arvand A;Kwan R;Chen GY;Gallagher E;Cheng G
MEKK 1是一种丝裂原活化蛋白激酶（MAPK 3 K），其活化MAPK JNK，并且是B细胞中微管激活剂诱导的细胞凋亡所需的。在这里，我们发现，通过细胞松弛素D和蛋白磷酸酶1/2A抑制剂冈田酸肌动蛋白破坏诱导的细胞凋亡也需要MEKK 1激活。为了阐明MEKK 1依赖性凋亡途径激活的功能要求，我们在MEKK 1内创建了突变。MEKK 1缺陷细胞补充MEKK 1含有突变的泛素相互作用基序（UIM），植物同源结构域（PHD），半胱天冬酶切割位点或激酶结构域在近内源性表达水平，并测试其对每种药物的敏感性。我们发现激酶活性和MEKK 1的PHD结构域都是JNK激活和通过引起细胞骨架破坏的药物有效诱导细胞凋亡所必需的。此外，我们发现MEKK 1的修饰及其定位依赖于PHD的完整性。
MEKK1 is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates the MAPK JNK and is required for microtubule inhibitor-induced apoptosis in B cells. Here, we find that apoptosis induced by actin disruption via cytochalasin D and by the protein phosphatase 1/2A inhibitor okadaic acid also requires MEKK1 activation. To elucidate the functional requirements for activation of the MEKK1-dependent apoptotic pathway, we created mutations within MEKK1. MEKK1-deficient cells were complemented with MEKK1 containing mutations in either the ubiquitin interacting motif (UIM), plant homeodomain (PHD), caspase cleavage site or the kinase domain at near endogenous levels of expression and tested for their sensitivity to each drug. We found that both the kinase activity and the PHD domain of MEKK1 are required for JNK activation and efficient induction of apoptosis by drugs causing cytoskeletal disruption. Furthermore, we discovered that modification of MEKK1 and its localization depends on the integrity of the PHD.
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DOI：
10.1093/jnci/djp235
发表时间：
2009-09-02
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Cardoso F;Bedard PL;Winer EP;Pagani O;Senkus-Konefka E;Fallowfield LJ;Kyriakides S;Costa A;Cufer T;Albain KS;ESO-MBC Task Force
通讯作者：
ESO-MBC Task Force
影响因子：
16
作者：
Ventura, JJ;H端bner, A;Davis, RJ
通讯作者：
Davis, RJ
影响因子：
4.8
作者：
Gallagher, ED;Gutowski, S;Cobb, MH
通讯作者：
Cobb, MH
影响因子：
3.6
作者：
Kolomeichuk, Sergey N.;Bene, Anca;Chambers, Timothy C.
通讯作者：
Chambers, Timothy C.
影响因子：
5.3
作者：
Kwan, R;Burnside, J;Cheng, GH
通讯作者：
Cheng, GH