Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells.
Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells.
复制标题
DOI：
10.1136/gut.2009.198903
复制
发表时间：
2010-03
期刊：
影响因子：
24.5
通讯作者：
Sahin-Tóth M
中科院分区：
文献类型：
--
作者：
Szmola R;Sahin-Tóth M
慢性胰腺炎是一种进行性胰腺炎性疾病，其特征在于腺泡细胞的永久性破坏。胰凝乳蛋白酶原C（CTRC）基因突变与慢性胰腺炎的发生有关。本研究的目的是探讨CTRC突变体是否会诱导胰腺腺泡细胞的内质网（ER）应激。地塞米松分化的AR 42 J大鼠腺泡细胞和新鲜分离的小鼠腺泡用携带野生型CTRC或p.A73T胰腺炎相关突变体的重组腺病毒转染。ER应激标志物通过逆转录-PCR和蛋白质印迹法进行评估。凋亡的特点是caspase-3/7活性和TUNEL法。腺泡细胞转染p.A73T突变体，但不是那些与野生型CTRC，发展显着的ER压力，作为判断升高的mRNA和蛋白水平的ER伴侣免疫球蛋白结合蛋白（BiP），增加剪接的X盒结合蛋白-1（XBP 1）mRNA和显着诱导的转录因子C/EBP同源蛋白（CHOP），ER压力相关的细胞凋亡的介质。与较高的CHOP表达一致，表达p.A73T突变体的AR 42 J细胞随着时间的推移而脱落，并显示出显著增加的半胱天冬酶-3/7活性和TUNEL染色。胰腺炎相关CTRC突变可显著增加胰凝乳蛋白酶原C诱发胰腺腺泡细胞ER应激的倾向。因此，CTRC突变的携带者可能在胰腺外分泌中发生ER应激的风险更高，这可能通过腺泡细胞凋亡导致实质损伤。
Chronic pancreatitis is a progressive inflammatory disorder of the pancreas characterized by permanent destruction of acinar cells. Mutations in the chymotrypsinogen C (CTRC) gene have been linked to the development of chronic pancreatitis. The aim of the present study was to explore whether CTRC mutants induce endoplasmic reticulum (ER) stress in pancreatic acinar cells. Dexamethasone-differentiated AR42J rat acinar cells and freshly isolated mouse acini were transfected with recombinant adenovirus carrying wild type CTRC or the p.A73T pancreatitis-associated mutant. ER stress markers were assessed by reverse transcription-PCR and western blotting. Apoptosis was characterized by caspase-3/7 activity and the TUNEL assay. Acinar cells transfected with the p.A73T mutant, but not those with wild-type CTRC, developed significant ER stress, as judged by elevated mRNA and protein levels of the ER chaperone immunoglobulin-binding protein (BiP), increased splicing of the X-box binding protein-1 (XBP1) mRNA and marked induction of the transcription factor C/EBP-homologous protein (CHOP), a mediator of ER stress-associated apoptosis. Consistent with higher CHOP expression, AR42J cells expressing the p.A73T mutant became detached over time and showed considerably increased caspase-3/7 activity and TUNEL staining. Pancreatitis-associated CTRC mutations can markedly increase the propensity of chymotrypsinogen C to elicit ER stress in pancreatic acinar cells. Thus, carriers of CTRC mutations may be at a higher risk of developing ER stress in the exocrine pancreas, which may contribute to parenchymal damage through acinar cell apoptosis.
登录
查看更多内容
影响因子：
24.5
作者：
Kereszturi E;Király O;Sahin-Tóth M
通讯作者：
Sahin-Tóth M
影响因子：
30.8
作者：
Rosendahl, Jonas;Witt, Heiko;Sahin-Toth, Miklos
通讯作者：
Sahin-Toth, Miklos
DOI：
10.1152/ajpgi.00471.2005
发表时间：
2006-08-01
影响因子：
4.5
作者：
Kubisch, Constanze H.;Sans, Maria Dolors;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.
影响因子：
3.9
作者：
TAKEMOTO, H;YOSHIMORI, T;TASHIRO, Y
通讯作者：
TASHIRO, Y
影响因子：
4.8
作者：
Mareninova, OA;Sung, KF;Gukovskaya, AS
通讯作者：
Gukovskaya, AS