Acute ablation of PERK results in ER dysfunctions followed by reduced insulin secretion and cell proliferation.
Acute ablation of PERK results in ER dysfunctions followed by reduced insulin secretion and cell proliferation.
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DOI：
10.1186/1471-2121-10-61
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发表时间：
2009-09-04
期刊：
影响因子：
--
通讯作者：
Cavener DR
中科院分区：
文献类型：
--
作者：
Feng D;Wei J;Gupta S;McGrath BC;Cavener DR
Perk（EIF 2 AK 3）的缺乏会导致人类的多种新生儿缺陷，称为沃尔科特雷利森综合征。Perk KO小鼠表现出相同的一系列缺陷，包括永久性新生儿糖尿病（PND）。我们先前表明，小鼠中的PND是由于β细胞增殖和胰岛素分泌的减少。本研究的目的是确定832/13 β细胞中PERK的急性消融是否重现了这些缺陷，并确定β细胞功能障碍的主要分子基础。通过腺病毒载体用显性阴性Perk转基因转导INS 1832/13转化的大鼠β细胞系。AdDNPerk-832/13 β细胞表现出胰岛素和MafA mRNA表达减少、胰岛素分泌减少和细胞增殖减少。尽管AdDNPerk-832/13 β细胞中胰岛素原含量降低，但胰岛素原异常保留在内质网中。Perk急性消融的时间研究显示，最早看到的缺陷是诱导表达两种ER伴侣蛋白，GRP 78/BiP和ERp 72。ERp 72和ERp 57的氧化状态也增加，表明ER的氧化还原状态不平衡。INS 832/13 β细胞中Perk的急性消融表现出Perk KO小鼠中观察到的所有主要缺陷，并揭示了关键ER伴侣蛋白的异常表达和氧化还原状态。ER伴侣/折叠酶ERp 72和GRP 78/BiP的失调发生在PERK功能消融后早期，表明ER分泌功能的变化可能引起其他缺陷，包括胰岛素基因表达、分泌和细胞增殖减少。
A deficiency in Perk (EIF2AK3) causes multiple neonatal defects in humans known as the Wolcott Rallison syndrome. Perk KO mice exhibit the same array of defects including permanent neonatal diabetes (PND). PND in mice was previously shown by us to be due to a decrease in beta cell proliferation and insulin secretion. The aim of this study was to determine if acute ablation of PERK in the 832/13 beta cells recapitulates these defects and to identify the primary molecular basis for beta cell dysfunction. The INS1 832/13 transformed rat beta cell line was transduced with a dominant-negative Perk transgene via an adenoviral vector. AdDNPerk-832/13 beta cells exhibited reduced expression of insulin and MafA mRNAs, reduced insulin secretion, and reduced cell proliferation. Although proinsulin content was reduced in AdDNPerk-832/13 beta cells, proinsulin was abnormally retained in the endoplasmic reticulum. A temporal study of the acute ablation of Perk revealed that the earliest defect seen was induced expression of two ER chaperone proteins, GRP78/BiP and ERp72. The oxidized states of ERp72 and ERp57 were also increased suggesting an imbalance in the redox state of the ER. Acute ablation of Perk in INS 832/13 beta cells exhibited all of the major defects seen in Perk KO mice and revealed abnormal expression and redox state of key ER chaperone proteins. Dysregulation of ER chaperone/folding enzymes ERp72 and GRP78/BiP occurred early after ablation of PERK function suggesting that changes in ER secretory functions may give rise to the other defects including reduced insulin gene expression, secretion, and cell proliferation.
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DOI：
10.1083/jcb.200602046
发表时间：
2006-06-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Forster ML;Sivick K;Park YN;Arvan P;Lencer WI;Tsai B
通讯作者：
Tsai B
影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
影响因子：
5.3
作者：
Di Jeso, B;Park, YN;Arvan, P
通讯作者：
Arvan, P
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
6.8
作者：
Dodson, G;Steiner, D
通讯作者：
Steiner, D