Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses
Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses
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DOI：
10.1016/s0006-2952(03)00484-2
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发表时间：
2003-10-15
影响因子：
5.8
通讯作者：
Oppermann, U
中科院分区：
文献类型：
--
作者：
Chang, NS;Doherty, J;Oppermann, U
人类WWOX基因编码一种推定的肿瘤抑制因子WW结构域氧化还原酶WOX1（也称为WWOX或FOR）。该基因的杂合性缺失（LOH）在前列腺癌、肺癌、乳腺癌和其他癌症中都有很高的频率。此外，在癌细胞中发现了许多异常的WWOX mRNA转录物。WOX1是一种促凋亡蛋白。对应激或凋亡刺激的反应。WOX1在Tyr33位点磷酸化，使其能够与活化的p53和JNK1形成复合物。p53/WOX1复合体易位到线粒体并进一步到细胞核介导细胞凋亡。由于核易位或Tyr33磷酸化而失活的WOX1突变体未能诱导细胞凋亡，表明WOX1是通过Tyr33磷酸化激活的。其次是核易位，是诱导细胞死亡的必要条件。WOX1与p53协同诱导细胞凋亡。相比之下。瞬时激活的JNK1诱导抗凋亡反应，这种保护活性抑制wox1诱导的细胞凋亡。综上所述。WOX1参与应激和凋亡反应，并可能调节p53和JNK1的激活。(C) 2003 Elsevier Inc.版权所有。
Human WWOX gene encodes a putative tumor suppressor WW domain-containing oxidoreductase WOX1 (also known as WWOX or FOR). A high frequency of loss of heterozygosity (LOH) of this gene has been shown in prostate, lung, breast and other cancers. In addition, numerous aberrant WWOX mRNA transcripts have been found in cancer cells. WOX1 is a proapoptotic protein. In response to stress or apoptotic stimuli. WOX1 became phosphorylated at Tyr33, which enabled its complex formation with activated p53 and JNK1. The p53/WOX1 complex translocated to the mitochondria and further to the nuclei to mediate apoptosis. WOX1 mutants, which were inactivated for nuclear translocation or Tyr33 phosphorylation, failed to induce apoptosis, indicating that activation of WOX1 via Tyr33 phosphorylation. followed by nuclear translocation, is essential for inducing cell death. WOX1 induced apoptosis synergistically with p53. In contrast. transiently activated JNK1 induced anti-apoptotic response, and this protective activity inhibited WOX1-induced apoptosis. Taken together. WOX1 is involved in stress and apoptotic responses, and is likely to regulate the activation of both p53 and JNK1. (C) 2003 Elsevier Inc. All rights reserved.