Chk2 splice variants express a dominant-negative effect on the wild-type Chk2 kinase activity
Chk2 splice variants express a dominant-negative effect on the wild-type Chk2 kinase activity
复制标题
DOI：
10.1016/j.bbamcr.2010.01.005
复制
发表时间：
2010-03-01
影响因子：
5.1
通讯作者：
Lonning, Per Eystein
中科院分区：
文献类型：
--
作者：
Berge, Elisabet Ognedal;Staalesen, Vidar;Lonning, Per Eystein
虽然人类基因组中蛋白质编码基因的大多数RNA转录本都受到生理性剪接的影响，但在癌症组织中，病理性剪接的报道越来越多。此前，我们鉴定了90种不同的Chk2剪接变体，Chk2是一种编码丝氨酸/苏氨酸激酶的基因，通过磷酸化和激活几种下游底物(如p53)来传播DNA损伤信号。CDC25A和CDC25C参与了细胞周期停滞和细胞凋亡。虽然其他基因的不同剪接形式已被报道对野生型分子产生显性-负向效应，但Chk2剪接蛋白变体的功能仍不清楚。在这里，我们评估了四种Chk2剪接蛋白的功能，这些剪接蛋白的mRNA剪接变体在人类乳腺癌中被确定。这些剪接变异体以核蛋白的形式稳定表达。两种剪接形式(Chk2 Delta 4和Chk2del(2-3))表达激酶活性，而变异体Chk2 Delta 11和Chk2isol基本上是不激活的。每个剪接变异体通过异源二聚作用削弱野生型Chk2的活性，而不依赖于内在的激酶活性。基于我们的发现，我们认为选择性剪接可能是抑制Chk2野生型功能的一种新机制。(C)2010爱思唯尔B.V.保留所有权利。
While the majority of RNA transcripts from protein-encoding genes in the human genome are subject to physiological splicing, pathological splicing is increasingly reported in cancer tissue. Previously, we identified >90 different splice variants of Chk2, a gene encoding a serine/threonine kinase propagating the DNA damage signal by phosphorylating and activating several downstream substrates like p53. Cdc25A, and Cdc25C involved in cell cycle arrest and apoptosis. While alternative splice forms of other genes have been reported to exert a dominant-negative effect on the wild-type molecules, the function of Chk2 splice protein variants is still unclear. Here we evaluated the function of four Chk2 splice proteins for which mRNA splice variants were identified in human breast carcinomas. These splice variants were stably expressed as nuclear proteins. Two splice forms (Chk2 Delta 4 and Chk2del(2-3)) expressed kinase activity while variants Chk2 Delta 11 and Chk2isol were essentially kinase inactive. Independent of intrinsic kinase activity, each splice variant impaired wild-type Chk2 activity through heterodimerization. Based on our findings, we suggest alternative splicing as a possible novel mechanism for repression of the Chk2 wild-type function. (C) 2010 Elsevier B.V. All rights reserved.