Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts.
Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts.
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DOI：
10.1111/acel.12300
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发表时间：
2015-02
期刊：
影响因子：
7.8
通讯作者：
Djabali K
中科院分区：
文献类型：
--
作者：
Gabriel D;Roedl D;Gordon LB;Djabali K
哈钦森-吉尔福德早衰症(HGPS，OMIM 176670)是一种罕见的多系统儿童早衰障碍，与LMNA基因突变有关。最常见的HGPS突变发生在LMNA基因第11外显子的G608G位置。这种突变导致前层蛋白A羧基末端50个氨基酸的缺失，被截断的蛋白质被称为孕激素。孕激素只经历正常翻译后修饰的一个子集，并永久保持法尼化。用法尼基转移酶抑制剂(FTI)和其他化合物挽救正常细胞表型的几次尝试已经导致了细胞的部分恢复。利用蛋白质组学，我们在这里报告了孕激素诱导HGPS核蛋白质组组成的变化，包括蛋白质降解途径的几个组成部分的变化。因此，蛋白酶体的活性和自噬在HGPS细胞中受到损害。为了恢复HGPS细胞的蛋白质清除，我们用萝卜硫素(SFN)处理HGPS培养物，这是一种从十字花科蔬菜中提取的抗氧化剂。我们确定SFN刺激正常和HGPS成纤维细胞的蛋白酶体活性和自噬。具体地说，SFN通过自噬增强孕激素清除，并逆转HGPS的特征表型变化。因此，SFN是治疗儿童HGPS的一种有前景的治疗途径。
Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS.
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影响因子：
82.9
作者：
Liu, BH;Wang, JM;Zhou, ZJ
通讯作者：
Zhou, ZJ
影响因子：
4.8
作者：
Liu, Yiyong;Wang, Youjie;Zou, Yue
通讯作者：
Zou, Yue
DOI：
10.1073/pnas.0511133103
发表时间：
2006-02-14
影响因子：
11.1
作者：
McClintock, D;Gordon, LB;Djabali, K
通讯作者：
Djabali, K
影响因子：
6
作者：
Blondel, Sophie;Jaskowiak, Anne-Laure;Nissan, Xavier
通讯作者：
Nissan, Xavier
DOI：
10.1073/pnas.0506001102
发表时间：
2005-09-06
影响因子：
11.1
作者：
Capell, BC;Erdos, MR;Collins, FS
通讯作者：
Collins, FS