Multiple developmental defects derived from impaired recruitment of ASC-2 to nuclear receptors in mice: Implication for posterior lenticonus with cataract
Multiple developmental defects derived from impaired recruitment of ASC-2 to nuclear receptors in mice: Implication for posterior lenticonus with cataract
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DOI：
10.1128/mcb.22.24.8409-8414.2002
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发表时间：
2002-12-01
影响因子：
5.3
通讯作者：
Lee, HW
中科院分区：
文献类型：
--
作者：
Kim, SW;Cheong, C;Lee, HW
ASC-2是最近分离的转录辅激活因子分子，通过多种转录因子（包括核受体）刺激转录激活。我们产生了ASC-2的一个有效的显性负性片段，包含与广泛的核受体结合的N末端LXXLL基序。该片段，称为DN 1，特异性地抑制内源性ASC-2在体内结合这些受体，而DN 1/m，其中LXXLL基序突变为LXXAA以消除受体相互作用，是惰性的。有趣的是，DNI转基因小鼠，而不是DN 1/m转基因小鼠表现出严重的小眼球和后囊畸形与白内障，以及在许多其他器官的各种病理生理表型。我们的研究结果提供了一个新的见解后囊型白内障的分子和组织病理学机制，并证明了ASC-2的重要性，作为一个关键的核受体在体内的转录辅激活因子。
ASC-2, a recently isolated transcriptional coactivator molecule, stimulates transactivation by multiple transcription factors, including nuclear receptors. We generated a potent dominant negative fragment of ASC-2, encompassing the N-terminall LXXLL motif that binds a broad range of nuclear receptors. This fragment, termed DN1, specifically inhibited endogenous ASC-2 from binding these receptors in vivo, whereas DN1/m, in which the LXXLL motif was mutated to LXXAA to abolish the receptor interactions, was inert. Interestingly, DNI transgenic mice but not DN1/m transgenic mice exhibited severe microphthalmia and posterior lenticorms with cataract as well as a variety of pathophysiological phenotypes in many other organs. Our results provide a novel insight into the molecular and histopathological mechanism of posterior lenticorms with cataract and attest to the importance of ASC-2 as a pivotal transcriptional coactivator of nuclear receptors in vivo.