PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice.
PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice.
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DOI：
10.1186/1471-2121-8-38
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发表时间：
2007-08-29
期刊：
影响因子：
--
通讯作者：
Cavener DR
中科院分区：
文献类型：
--
作者：
Iida K;Li Y;McGrath BC;Frank A;Cavener DR
人类和小鼠中 PERK eIF2α 激酶的缺陷会导致出生后外分泌胰腺萎缩以及其他器官和组织的严重生长和代谢异常。为了确定外分泌胰腺萎缩是否是由于细胞自主缺陷所致，专门消除了小鼠外分泌胰腺腺泡细胞中的 Perk 基因。我们发现，腺泡细胞中 PERK 的表达是维持其活力所必需的，但对于正常的蛋白质合成和分泌来说不是必需的。根据对培养成纤维细胞的研究，PERK 缺陷小鼠的外分泌胰腺萎缩先前被归因于不受控制的 ER 应激，随后导致细胞凋亡。然而，我们没有发现内质网扰动或内质网应激的证据，并表明腺泡细胞会死于非凋亡形式的细胞死亡，即肿瘤，这与明显的炎症反应和胰腺炎应激反应基因的诱导有关。我们还发现，携带 PERK 下游靶点 ATF4 敲除突变的小鼠表现出由发育缺陷引起的胰腺缺陷，而 ATF4 转录靶点 CHOP 被消除的小鼠具有正常的外分泌胰腺。我们得出结论，PERK 通过调节腺泡细胞的细胞活力来调节外分泌胰腺的分泌能力。
Deficiency of the PERK eIF2α kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. To determine if the exocrine pancreatic atrophy is due to a cell-autonomous defect, the Perk gene was specifically ablated in acinar cells of the exocrine pancreas in mice. We show that expression of PERK in the acinar cells is required to maintain their viability but is not required for normal protein synthesis and secretion. Exocrine pancreatic atrophy in PERK-deficient mice was previously attributed to uncontrolled ER-stress followed by apoptotic cell death based on studies in cultured fibroblasts. However, we have found no evidence for perturbations in the endoplasmic reticulum or ER-stress and show that acinar cells succumb to a non-apoptotic form of cell death, oncosis, which is associated with a pronounced inflammatory response and induction of the pancreatitis stress response genes. We also show that mice carrying a knockout mutation of PERK's downstream target, ATF4, exhibit pancreatic deficiency caused by developmental defects and that mice ablated for ATF4's transcriptional target CHOP have a normal exocrine pancreas. We conclude that PERK modulates secretory capacity of the exocrine pancreas by regulating cell viability of acinar cells.
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