Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway
Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway
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具有扩展的多聚谷氨酰胺重复序列的亨廷顿蛋白影响 Jab1-p27(Kip1) 通路
DOI：
10.1016/j.nbd.2012.03.008
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发表时间：
2012-06-01
影响因子：
6.1
通讯作者：
Dorsman, J. C.
中科院分区：
文献类型：
--
作者：
Cong, S. Y.;Pepers, B. A.;Dorsman, J. C.
聚谷氨酰胺重复序列的扩增是至少九种遗传性人类神经退行性疾病的原因，包括亨廷顿舞蹈病（HD）。扩增亨廷顿蛋白（expanded huntingtin, htt）对转录辅激活因子CBP的调控在HD的分子发病机制中起着重要作用，这一观点已被广泛接受。在这项研究中，我们报道了一个新的靶点，即与CBP共享dna序列特异性转录因子靶点的转录辅激活因子Jun激活结构域结合蛋白1 （Jab1）。Jab1还在细胞周期蛋白依赖性激酶抑制剂和推定的转录辅助因子p27（Kip1）的降解中起主要作用。我们发现Jab1在与突变体htt扩增的聚谷氨酰胺片段或n端片段共表达时聚集。此外，Jab1的共激活子功能被单独的聚集扩展聚谷氨酰胺和突变体htt抑制。突变体htt的抑制作用甚至早于微观聚集的出现。在外显子1 HD细胞模型中，我们发现内源性Jab1可以被募集到聚集体中，并且这伴随着p27（Kip1）的积累。在HD患者的大脑中也发现了p27（Kip1）的积累。各种机制对Jab1的抑制加上p27（Kip1）在晚期的增加可能具有重要的转录作用。此外，对Jab1-p27（Kip1）通路的干扰可能有助于降低HD患者的癌症发病率，也可能与了解聚谷氨酰胺疾病的分子发病机制有关。(C) 2012爱思唯尔公司版权所有。
Expansion of polyglutamine repeats is the cause of at least nine inherited human neurodegenerative disorders, including Huntington's disease (HD). It is widely accepted that deregulation of the transcriptional coactivator CBP by expanded huntingtin (htt) plays an important role in HD molecular pathogenesis. In this study, we report on a novel target of expanded polyglutamine stretches, the transcriptional coactivator Jun activation domain-binding protein 1 (Jab1), which shares DNA-sequence-specific transcription factor targets with CBP. Jab1 also plays a major role in the degradation of the cyclin-dependent-kinase inhibitor and putative transcription cofactor p27(Kip1). We found that Jab1 accumulates in aggregates when co-expressed with either expanded polyglutamine stretches or N-terminal fragments of mutant htt. In addition, the coactivator function of Jab1 was suppressed both by aggregated expanded polyglutamine solely and by mutant htt. Inhibition by mutant htt even preceded the appearance of microscopic aggregation. In an exon 1 HD cell model, we found that endogenous Jab1 could be recruited into aggregates and that this was accompanied by the accumulation of p27(Kip1). Accumulation of p27(Kip1) was also found in brains derived from HD patients. The repression of Jab1 by various mechanisms coupled with an increase of p27(Kip1) at late stages may have important transcriptional effects. In addition, the interference with the Jab1-p27(Kip1) pathway may contribute to the observed lower incidence of cancer in HD patients and may also be relevant for the understanding of the molecular pathogenesis of polyglutamine disorders in general. (C) 2012 Elsevier Inc. All rights reserved.